Abstract
According to recent studies, migraine affects more than 1 billion people worldwide, making it one of the world’s most prevalent diseases. Although this highly debilitating illness has been known since ancient times, the first therapeutic drugs to treat migraine, ergotamine (Gynergen) and dihydroergotamine (Dihydergot), did not appear on the market until 1921 and 1946, respectively. Both drugs originated from Sandoz, the world’s leading pharmaceutical company in ergot alkaloid research at the time. Historically, ergot alkaloids had been primarily used in obstetrics, but with methysergide (1-methyl-lysergic acid 1′-hydroxy-butyl-(2S)-amide), it became apparent that they also held some potential in migraine treatment. Methysergide was the first effective prophylactic drug developed specifically to prevent migraine attacks in 1959. On the basis of significantly improved knowledge of migraine pathophysiology and the discovery of serotonin and its receptors, Glaxo was able to launch sumatriptan in 1992. It was the first member from the class of triptans, which are selective 5-HT1B/1D receptor agonists. Recent innovations in acute and preventive migraine therapy include lasmiditan, a selective 5-HT1F receptor agonist from Eli Lilly, the gepants, which are calcitonin gene-related peptide (CGRP) receptor antagonists discovered at Merck & Co and BMS, and anti-CGRP/receptor monoclonal antibodies from Amgen, Pfizer, Eli Lilly, and others.
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This review is not intended to be read in a linear fashion. If you are interested in a particular topic, please feel free to jump directly to the section of interest. The content ranges from 1. Introduction 2. Description of Migraine 3. Treatment of Migraine attacks 4. Chemical Syntheses of Migraine Drugs 5. Migraine and Natural Medicine | |
In this review, we emphasize on total and industrial syntheses. If your focus is on the pathophysiology or pharmacology of migraine, please consult also the relevant literature cited. | |
As you browse through this review, you will find numerous infoboxes that contain interesting and sometimes entertaining information, but they are not essential to the story and can be skipped. | |
In order to simplify retracing the numerous building blocks, the drawings of most chemical syntheses are in color. The color code is consistent within a total synthesis, but not between two different ones. |
Introduction
History of migraine
William Dunbar (about 1460–1530) was a distinguished bard (Scottish: Markar) in the service of James IV of Scotland (1473–1513) (Fig. 1) [1]. In the first stanza of his brief Middle Scots poem “On his heid-ake” he bequeathed us a late medieval description of the headache phase of migraine, authentically featuring the debilitating effects on his own body: photophobia and pain [2,3,4]. In the second and third stanzas, Dunbar thoroughly captured the postdrome phase [5] (literally hangover or aftermath) of migraine, such as fatigue, dullness, and distress, and the inability to find the right words.
On his heid-ake My heid did yak yester nicht, This day to mak that I na micht. So sair the magryme dois me menyie, Perseing my brow as ony ganyie, That scant I luik may on the licht. | On his headache [6] My head did ache last night, so much that I cannot write poetry today. So painfully the migraine does disable me, piercing my brow just like any arrow, that I can scarcely look at the light. |
And now, schir, laitlie eftir mes To dyt thocht I begow the to dres, The sentence lay full evill till find, Unsleipit in my heid behind, Dullit in dulnes and distres. | And now, Sire, shortly after mass, though I tried to begin to write, the sense of it lurked very hard to find, deep down sleepless in my head, dulled in dullness and distress. |
Full oft at morrow I upryse Quhen that my curage sleipeing lyis. For mirth, for menstrallie and play, For din nor danceing nor deray, It will not walkin me no wise. | Very often in the morning I get up when my spirit lies sleeping. Neither for mirth, for minstrelsy and play, nor for noise nor dancing nor revelry, it will not awaken in me at all. |
Actually, the first artifacts as well as human remains relating to headache and migraine are much older, originating in prehistoric times. As early as in the Neolithic era 9000 years ago, trepanation, the removal of a piece of bone from the skull, might have been an ultimate surgical treatment of this condition [7]. Sumerian cuneiform inscriptions and Egyptian papyri, e.g., the Ebers papyrus (c. 1550 BC) and the Hearst papyrus (2000 BC)) suggest that migraine might have been viewed as a spiritual entity rather than an ailment [8, 9]. Mesopotamians attributed migraine to Ti’u, the evil spirit of headache, and its appeasing with medicinal formulas or its release by trepanation were considered appropriate treatments (Fig. 2) [10, 11].
The brain itself does not feel pain, because it lacks pain receptors. However, in most other inner parts of the head nociceptors are found, including the eyes, ears, teeth, the lining of the mouth, the cranial and spinal nerves, the head and neck muscles, the extracranial arteries, the middle meningeal artery, the dural venous sinuses, the meninges, and parts of the brainstem [12].
Hippocrates of Kos (460–377 BC) conceived all illnesses, including headache, as an imbalance of natural factors and conceptualized the treatment as a rebalancing of these disturbances. He was the first physician describing the visual symptoms resembling a migraine aura in The seventh book of epidemics about his patient called Phaenix:
Phaenix’s complaint was of such a nature that flashes like lightning seemed to dart from his eye, and generally his right eye. Not long after, a violent pain seized his right temple, and then his whole head and neck. The back part of his head at the vertebrae swelled; and the tendons were upon the stretch and hard. Now if he attempted to move his head, or to open his teeth, a pain seized him from the violence of the stretch. Vomitings, whenever they happened, removed the pains now mentioned, or made them easier. Bleeding was also of service; and hellebore draughts brought away all sorts of humors, especially porraceous [13].
Aulus Cornelius Celsus (25 BD-50 AD) recognized in migraine a lifelong disorder, which might be triggered by numerous factors.
Aretaeus of Cappadocia (81–138 AD) was able to differentiate three types of headache, among those heterocrania, a paroxysmal headache on one side of the head, which frequently is accompanied by nausea, vomiting, and photophobia.
Galen of Pergamon (c. 129 to c. 199 AD), personal physician to the Roman emperor Marcus Aurelius (121–180 AD), coined the term hemicrania [from hemikranion (Gr.): half skull] for recurrent painful attacks affecting almost half of the head. He also supposed that the throbbing pain might be caused by arterial pulsation (Fig. 3).
Description of migraine
Classification of headache disorders
Today, we have a detailed classification of headache including a distinct delineation of the clinical syndrome of migraine based on clear diagnostic criteria. Cephalalgia, synonym to headache, is a symptom that refers to any type of pain located in the head, face, or neck. According to the International Classification of Headache Disorders, the sum of more than 200 types of headache can be divided into two large categories of primary and secondary headaches [52]. Ninety percent of all headaches are primary headaches. Albeit causing significant daily pain and disability, in most cases they are benign. Examples are migraine, hemicrania continua, cluster headaches, trigeminal neuralgia, primary stabbing headaches, primary sex headaches, and hypnic headaches [53]. In contrast, secondary headaches are often caused by an underlying disease, such as an infection, head injury, vascular disorders, brain bleed, stomach irritation, or tumors, and should be considered as warning signs.
Types of migraine
Migraines, according to its specific features and associated symptoms, can be divided into two major classes: migraine without aura and migraine with aura [52, 61].
The common migraine is a migraine not accompanied by an aura.
The classic migraine involves the experience of an aura episode, which in some varieties as is in the case of familial hemiplegic migraine and sporadic hemiplegic migraine, can be accompanied by motor weakness. Basilar-type migraine involves other symptoms of brainstem-related difficulties, such as dysarthria (motor speech disorder), vertigo, and ringing in the ears.
The cyclic vomiting syndrome (formerly called abdominal migraine) is a disorder most commonly diagnosed in children. It comprises the symptoms of abdominal pain, nausea, cyclical vomiting, light sensitivity, benign paroxysmal vertigo, and headaches.
In the case of retinal migraine, the migraine headache is accompanied by visual disturbances or even temporary blindness in one eye.
Chronic migraine meets all diagnostic criteria for migraine headache, but an episode lasts at least 15 days per month for more than 3 consecutive months.
Phases of a migraine episode
A typical migraine attack can be divided into four distinguishable phases, although not all phases are necessarily experienced.
The prodrome phase might onset a couple of days to a few hours before the experience of pain. The symptoms can range from craving for certain foods to constipation or diarrhea, stiff muscles, sensitivity to noise or smells, fatigue, altered mood, irritability, and depression or euphoria.
The aura is a transient neurological phenomenon that can emerge before the pain phase. The symptoms comprise auditory hallucinations, delusions (a fixed belief that is not amenable to change considering conflicting evidence), sensory and motoric effects (tingling, numbness, loss of position sense), but most frequently visual disturbances. The visual disorders may consist of scintillating scotoma (alterations in the field of vision, often zigzagging lines) and hemianopsia (blurring and loss of vision in parts of the visual field) (Fig. 10).
The pain phase usually arises gradually and aggravates over time. Typically, the headache is unilateral, throbbing, and of moderate to severe intensity. Remarkably, the throbbing is not in phase with the pulse. Physical exercise often worsens pain. The pain phase is frequently accompanied by irritability, fatigue, nausea, vomiting, sensitivity to light, sound, and smells. However, silent migraine episodes are also known, in which the aura is not continued by a pain phase.
The postdrome phase follows once the acute headache has settled. Many patients feel tired or a hangover, accompanied with cognitive difficulties, impaired thinking, gastrointestinal symptoms, weakness, and mood changes. Some feel unusually refreshed or euphoric, whereas others experience depression and malaise [62].
Triggers of migraine
Migraine attacks might be triggered by multiple factors [63], including stress, fatigue [64], certain foods, and weather, although empirical data remain elusive [65,66,67]. However, there is also some evidence associating migraine episodes with post-traumatic stress disorder and abuse [68], as well as with hormonal influences, e.g., menstruation [69] and pregnancy [70].
Genetics
Aside from environmental triggers, genetic factors might also contribute to the likelihood of experiencing migraines [71, 72]. It is generally accepted that migraine might run in families. Familial hemiplegic migraine, for example, is inherited in an autosomal dominant way. Of the four genes associated with this type of migraine, three of them are involved in ion transport, and the fourth encodes an axonal protein associated with the exocytosis complex [73]. Another example is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL syndrome), caused by mutations of the Notch 3 gene on chromosome 19, which may start migraine attacks with aura [74]. Finally, more recent studies suggest a contribution of transient receptor-potential melastatin 8 (TRPM8) to migraine [75]. TRPM8 is predominately expressed in cutaneous tissue and serves as a cold receptor, but it is also found on deep visceral afferents, such as the meninges, where temperature is not likely a stimulus. It has been suggested that activation of meningeal TRPM8 by exogenous agonists can cause headaches. Moreover, several recent studies have revealed that single-nucleotide polymorphisms of TRPM8 are consistently associated with the susceptibility to both migraine with and without aura [76].
Pathophysiology
Vascular theory of migraine
Despite enormous efforts in research and public awareness, our knowledge of migraine pathophysiology remains limited. The throbbing, pulsating pain of migraine, thought to be caused by periodical dilations of the blood vessels, is attributed to Galen and was reproposed by Thomas Willis in the late seventeenth century [77]. But it was not until the early 1940s that Harold G. Wolff (1898—1962) [78, 79], neurologist at the New York Hospital—Cornell Medical Center, demonstrated that the intensity of migraine is closely linked to the pulsating branches of the external carotid arteries (Fig. 11).
Decreasing the amplitude of pulsation alleviates headache. The same effect was achieved using ergot alkaloids to induce vasoconstriction of temporal and middle meningeal arteries, whereas vasodilators, such as nitroglycerin, can trigger migraine attacks [80]. These observations laid the foundation for what later became known as the vascular theory of migraine. It centers on the concept that ischemia, as a result of intercranial vasoconstriction triggered by endothelin 1, which causes the aura [81]. The following rebound vasodilation and activation of perivascular nociceptive nerves lead to the headache.
Over the years, Wolff’s theory has been elaborated and modified, but despite some shortcomings still constitutes the generally accepted model on vascular contributions to migraine [83, 84].
In particular, the weaknesses are:
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The features of the prodrome phase cannot be readily explained by vascular effects.
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There are some drugs that are effective in the treatment of migraine but do not affect blood vessels.
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The majority of migraineurs, about 2/3, do not experience auras.
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Intracranial blood flow patterns are inconsistent with the vascular theory.
From today’s holistic concept, the pathophysiology comprises a complex series of neuronal and vascular events leading finally to the symptoms of migraine [85]. According to the neurovascular theory, migraine results primarily from pathological neurogenic processes. Abnormal vascular effects are an epiphenomenon. They are not the cause but a consequence of this malfunction [86, 87].
Neurovascular theory of migraine
The roots of the neurovascular theory might also be traced back to the early 1940s. In 1941, the American psychologist Karl Spencer Lashley (1890–1958) reported on a scotoma he had experienced in the course of a migraine aura. He calculated a spreading velocity of the neuronal disturbance over his vision cortex in the range of 2–3 mm/min [88].
Three years later, the Brazilian biologist Aristides de Azevedo Pacheco Leão (1914–1993) published a seminal paper on the “Spreading depression of activity in the cerebral Cortex” of a rabbit (Fig. 12) [89]. Later spreading depression of cortical activity has been observed in a wide variety of species from cephalopods and locusts to numerous vertebrates, including rats, hamsters, pigs, and humans [90].
As early as in 1958, the Canadian neuroscientist Peter Milner (1919–2018) from McGill University in Montreal assumed a possible correspondence between the scotomas of migraine and cortical spreading depression of Leão [91].
Since these early findings, a host of even highly dedicated physicians developed the neurovascular theory of migraine and thereby laid the foundation for an effective treatment of this abundant and debilitating ailment. From our current perspective, the phases of a migraine attack are associated with different physiological processes [92, 93].
Premonitory phase
During the premonitory phase, which might begin as early as 3 days before the onset of the headache phase, a complex interplay between various brain regions, including the brainstem and the hypothalamus, leads to nociceptive signaling. There are two main theories of how this might happen:
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1.
Increasing parasympathetic tone activates meningeal nociceptors
The onset of the premonitory phase is caused by migraine triggers, which changes homeostasis and activates nociceptive pathways through an increased parasympathetic tone. This hypothesis is supported by the observation that indicators of an altered autonomic function, such as nausea, vomiting, thirst, lacrimation, nasal congestion, and rhinorrhea, are also features of a migraine attack.
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2.
Modulation of nociceptive signals from the thalamus to the cortex
A delicate balance of neurotransmitter/neuropeptides from the hypothalamus and the brainstem regulates the firing of relay trigeminovascular neurons. Depending on the type of neurotransmitter, whether it is excitatory or inhibitory, it ultimately modulates the firing of thalamic trigeminovascular neurons and thus determines the transmission of nociceptive signals to the cortex.
Aura/non-aura phase
In one-third of all migraine attacks the premonitory phase is followed by an aura. The cortical spreading depression, which is a decreased activity of neurons and glial cells, is caused by the release of potassium ions and excitatory glutamate from neurons leading to transient depolarization and in turn triggering the release of more neurotransmitters. As a result, spreading waves of electrophysiological hyperactivity are followed by waves of inhibition characterized by a negative change of the DC potential by 20–35 mV. They slowly propagate across the cortical surface, but also in subcortical regions, with a speed of 1.5–9 mm/min and coincide with the initiation and progression of aura symptoms lasting for about 30 min [94, 95].
Spreading depolarization decreases metabolism, causing a condition in which the total volume of blood is reduced (oligemia). Positron emission tomography (PET) has shown that blood flow is moderately reduced during an aura episode. It might be a question of a certain threshold to produce this symptom. In cases where this threshold is not reached, the patient experiences a migraine attack without aura [96].
Headache phase
The throbbing pain of a migraine headache results from activation of the trigeminovascular pathway (a network of nerves linked to blood vessels in the head). There is some evidence from animal studies that ATP, potassium ions, glutamate, and nitric oxide (NO) are released in the course of cortical spreading depression. In addition, genes encoding cyclooxygenase-2, tumor necrosis factor alpha, interleukin-1β, galanin, and metalloproteinases are upregulated. The latter lead to the leakage of the blood–brain barrier, facilitating sensitization of the dural perivascular trigeminal afferent endings by potassium ions, adenosine, and nitric oxide [94]. However, in all these events, the pituitary adenylate cyclase-activating polypeptide (PACAP-38) and the calcitonin gene-related peptide (CGRP), also released by cortical spreading depression, play a pivotal role [97, 98].
It has been shown that the intravenous administration of neuropeptide PACAP-38, comprising 38 amino acids, can induce migraine [99]. It leads to dural mast cell degranulation and thereby liberation of inflammatory mediators, such as bradykinin, histamine, prostaglandin E2, and cytokines [100], and causes vasodilation of the middle meningeal artery [101].
Like PACAP-38, the calcitonin gene-related peptide can also induce migraine attacks. During the headache phase, elevated concentrations of CGRP were found in jugular venous blood. The 37 amino acid neuropeptide is a potent vasodilator at the meningeal blood vessels and may also cause sterile inflammation. Mediated by glutaminergic signaling, it acts as a neurotransmitter that enhances synaptic transmission and activates meningeal nociceptors. Once activated, the peripheral trigeminovascular neurons become sensitized to dural stimuli. The increased sensitivity to sensory stimulation is responsible for the characteristic throbbing pain, and the aggravation of pain by bending over or coughing. In the majority of cases, the headache goes along with nausea, phonophobia, and photophobia caused by a general neuronal hyperexcitability including brainstem reflexes and somatosensory, auditory, and visual stimuli. [92].
Postdrome phase
In adults the headache phase usually lasts up to 72 h, whereas in children it often persists only for less than 1 h [102, 103]. The following postdrome phase is marked by symptoms such as a sore feeling in the area where the headache was, tiredness, cognitive difficulties, gastrointestinal symptoms, and mood changes. Some migraineurs feel refreshed or euphoric, whereas others suffer from depression and malaise (Fig. 13) [104, 105].
Treatment of migraine attacks
Ergotamine
Since medieval times an enormous number of remedies were used therapeutically in the attempt to relieve the headache caused by migraine. None proved consistently effective. It was not until 1862 that E. Moretti reported the “Story of a scurvy headache cured by the internal use of ergot extract” (“Storia di una cefalalgia scorbutica guarita mediante l’uso interno dell’estratto di segale cornuta”) in an Italian journal [120]. It was the English surgeon Edward Woakes (1837–1912) in Luton, who first recommended “ergotine,” an extract of ergot of rye (Claviceps purpurea, syn. Secale cornutum, typically used in obstetrics for centuries) as a vasoconstricting agent for the treatment of migraine headache in 1868 [121,122,123]. Already in the 1850s, Charles-Édouard Brown-Séquard FRS (1817–1894), a Mauritian physiologist and neurologist, and the French physiologist Claude Bernard (1813–1878) had hypothesized on migraine as a result of vasoconstriction, while the German physician and physiologist Emil Heinrich du Bois-Reymond (1818–1896) had thought it might be caused by vasodilation [124]. It was only in 1867 when Friedrich Wilhelm Möllendorff, a medical practitioner in Berlin [125], provided experimental evidence of vasodilation in course of a migraine attack, applying an ophthalmoscope invented by his colleague Hermann Ludwig Ferdinand von Helmholtz (1821–1894) [126]. It seems reasonable to assume that Möllendorff’s observation had a decisive influence on Woakes’ concept of migraine. On the other hand, Woakes’ method facilitated by numerous German-language publications, spread rapidly in Germany as well [127,128,129,130]. However, the remedy gained acceptance only after Arthur Stoll (1887–1971), a Swiss biochemist at Sandoz (now Novartis), isolated pure ergotamine tartrate in 1918, which brought about a standardized drug with reliable properties and predictable effects [131]. It was brought to the market by Sandoz in 1921 under the tradename “Gynergen” for the treatment of postpartum bleeding and subsequently also for migraine treatment [80, 132, 133].
In 1935, Arthur Stoll reported on another main alkaloid in Claviceps purpurea, lysergic acid β-propanolamide, which would obtain some relevance in obstetrics to facilitate delivery of the placenta and to prevent bleeding after childbirth, but also as a lead structure for some semisynthetic ergot drugs [134]. In the same year, John Chassar Moir (1900–1977), at that time First Assistant to the Obstetric Unit of the University College Hospital, London together with H. Ward Dudley published on the same subject. They comprehensively described isolation, chemical properties, and pharmacology of the new substance and proposed the name “ergometrine” [135]. The first partial synthesis was performed by Arthur Stoll and Albert Hofmann in 1937, by reacting the azide of lysergic acid with (2S)-amino propanol (Fig. 15) [136].
Ergotamine-derived drugs
The first artificial migraine remedy was dihydroergotamine, simply obtained by catalytic hydrogenation of ergotamine. The active agent was claimed by Sandoz in 1942 and introduced to the market in 1946. It was sold under the brand names “Dihydergot,” “D.H.E. 45,” “Migranal,” “Ergont,” “Ikaran,” and others. In 2013, the European Medicines Agency recommended restrictions of ergot alkaloids to prevent migraine headaches, since the risks are greater than the benefits in this indication compared to more selective and readily available drugs [192].
Today, though it was was not known at that time, the antimigraine activity of dihydroergotamine can be explained by its action as an agonist at the serotonin receptors 5-HT1B, 5-HT1D, and 5-HT1F.[193]. Unfortunately, it has also some interactions with adrenergic and dopamine receptors, but most unfavorably, it is also an agonist at the serotonin 5-HT2B receptor, which has been associated with cardiac valvulopathy [194].
The first effective migraine prophylactic methysergide evolved on the pursuit of better drugs in obstetrics, to stop postpartum hemorrhage. Out of many analogs of ergometrine, Albert Hofmann and Franz Troxler synthesized the (S)-butanolamide of lysergic acid, methylergonovine, which proved to be superior in its pharmacological properties compared to the natural product. It was used worldwide in obstetrics under the brand name “Methergine.”
Later, however, Hofmann and Troxler obtained, by simple methylation of methylergonovine, methysegide (1-methyl-lysergic acid-1′-hydroxy-butyl-(2S)-amide), a substance with enhanced specific antiserotonin activity, which was marketed by Sandoz in the early 1960s as the first drug for the prevention of migraine (Fig. 21) [195, 196, 197].
Its clinical development can be traced back to Harold Wolff’s theory of vasodilation in migraine. It is less known that Harold Wolff himself also searched for a perivascular factor that could damage blood vessels and increase pain sensitivity in course of a migraine attack [198]. Already in 1938, he published a remarkable article on the mechanism of migraine headache and the action of ergotamine [44, 199].
After the discovery of serotonin in 1948, indications gradually accumulated that serotonin might play a pivotal role in migraine headaches [200]. Serotonin, which was also found in brain extracts, proved to be a strong vasoconstrictor [201]. In the late 1950s, LSD turned out to be the most effective serotonin antagonist, but could not be applied because of its hallucinogenic side effects [202]. On the other hand, methysergide proved to be similar effective, but beneficially lacking the psychotropic effects [203]. It was introduced in the clinic in 1959 by the Italian neurologist Federigo Sicuteri [204]. He succeeded in demonstrating the remarkable prophylactic and therapeutic properties of methysergide. However, it took only a few years until severe side effects, among those cardiac and pulmonary fibrosis, were discovered, which ultimately led to the discontinuation of the drug by Novartis [205–207].
The pharmacodynamics of methysergide is much more intricate, as was known at the time. Methysergide binds to the serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 receptors as well as to the α2A-, α2B-, and α2C-adrenergic receptors [208]. Its interaction with the 5-HT1 receptors is agonistic or partial agonistic, while it acts as an antagonist at the 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors [209,210,211,212,213].
Even so, the beneficial antimigraine effects of methysergide in humans are related to its metabolic degradation into methylergonovine [214, 215]. Methylergonovine, acting as an agonist, is about ten times more potent at the 5-HT1B and 5-HT1D receptors [216]. Unfortunately, it is also an agonist or partial agonist at the 5-HT2A and 5-HT2B receptors, which in the first case is associated with psychedelic effects [217, 218] and in the second case with cardiac valvulopathy [219]. However, the real issue is that the 5-HT2A and 5-HT2B receptor antagonism of methysergide cannot overcome the serotonin receptor agonism of methylergonovine due to its fast metabolism [220].
Triptans
The search for improved migraine drugs commenced at Allen & Hanburys, a subsidiary of Glaxo at Ware, a small-town north of London in 1972. A recently hired young pharmacologist, Patrick P. A. Humphrey [254] and his graduate assistant Eira Apperley, founded their work on both Harold Wolff’s observation that ergotamine administered intravenously can abort migraine attacks, which is correlated with reduced temporal artery pulsation, and that the endogenous neurotransmitter serotonin may act in a similar way. The involvement of serotonin in a migraine episode was underpinned by Sicuteri, who showed that its metabolite, 5-hydroxyindolylacetic acid, is present in urine after an attack [255, 256]. Humphrey assumed that serotonin should act as a vasoconstrictor on the cranial vessels outside the brain because it is incapable of crossing the blood–brain barrier. However, it could not be used as drug by itself due to many side effects. Thus, the medical need for improved migraine treatment was a preferentially orally bioavailable agent, acting selectively at the cranial vessel as a vasoconstrictor.
In 1974, Pramod Saxena [257], a pharmacologist at the Medical Faculty Rotterdam (now Erasmus Medical Center), reported that intravenous methysergide produced a very localized cranial vasoconstriction leading to reduced carotid blood flow without any effect on blood pressure [258]. Patrick Humphrey went on to show that this effect was mediated by a then unknown vascular serotonin receptor, now known as 5-HT1B receptor. At the time, little was known about the diversity of serotonin receptors. Notwithstanding all these uncertainties, in the 1970s, Glaxo launched a research program in search for serotonin analogs, which may selectively activate the 5-HT1B receptor. After many hurdles and pitfalls, the first compound that turned out to be effective in a dog model was 5-carboxamidotryptamine (AH21467) [258]. However, by stimulating another 5-HT-receptor, later assigned as 5-HT7, it also caused vasodilatation, and was therefore deemed to be insufficiently selective. The next hit the research team found was AH25086 [259], indeed a selective agonist, but was found to be unsuitable for oral administration (due to its poor absorbance in the gastrointestinal tract resulting from its high lipophobicity [260]) and, therefore, less suitable for clinical development. Much more effort had to be spent before Patrick Humphrey and his team finally found GR-43175, which was named sumatriptan and became available for clinical use in 1991. It proved to be an active ingredient with high selectivity and sufficient oral bioavailability. Sumatriptan was initially introduced in the Netherlands in 1992 and has been marketed in the USA since 1993 [261, 262]. In subsequent years, numerous companies brought more triptans to the market (Table 3) [263].
All triptans share the indole structure and an almost equidistant amino group with serotonin. The main structural difference of the triptans is the side chain at position 5. It ranges from sulfonamides and sulfones, via heterocycles, such as triazole, 2-oxazolidone, to a carboxamide.
All triptans exhibit high affinity to the 5-HT1B and 5-HT1D receptors, and to some extend also to the 5-HT1F receptor [264, 265].
The 5-HT1B and 5-HT1D receptors are very similar, thus they bind the almost same pharmacophore (Fig. 25) [239, 266,267,268]. The 3D QSAR analysis-based model consists of:
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An indole scaffold, interacting via π stacking with the aromatic amino acid Phe316
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An ammonium group (a donor of a hydrogen bond), forming a salt bridge with Asp118
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A hydrogen bond of Thr202 with the sulfonamide moiety
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A hydrophobic cage around the ammonium group by Trp114, Tyr346, and Trp343
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Dispersive interactions with Leu115
It is generally accepted that triptans exert their activity by numerous mechanisms of action, which may be additive in their ability to abort migraine [270, 271]:
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By activating the 5-HT1B receptors, the triptans act as potent vasoconstrictors on the vascular smooth muscles of the pain-sensitive intracranial, extracerebral vessels, i.e., of the human middle meningeal arteries.
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They prevent the release of vasoactive peptides by activation of presynaptic 5-HT1D receptors, including substance P and the calcitonin gene-related peptide (CGRP) [235, 272, 273]
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The triptans inhibit nociceptive neurotransmission within the trigeminocervical complex (which contains the major relay neurons for nociceptive afferent input from the dura and cervical structures).
The introduction of the triptans in the 1990s represented a major step forward in the treatment of migraine attacks. Nevertheless, this class of compounds also had some disadvantages resulting from its mode of action, which limited its efficacy and application.
It has been described that in up to 25% of the migraineurs none of the triptans is effective [274, 275]. On the flip side, continued migraine treatment with triptans can be result in medication overuse headache [276] and a certain propensity for recurrence.
Considering that 5-HT1B receptors are not only widely distributed throughout the central nervous system and cerebral blood vessels but also in pulmonary and coronary arteries, there is a strict contraindication for triptans in patients suffering from cardiovascular and/or cerebrovascular diseases, and/or uncontrolled hypertension. Furthermore, triptans pose some risks to patients suffering from particular forms of hemiplegic migraine, and during pregnancy and breastfeeding. Thus, there was an ongoing medical need for even more tolerable drugs.
Fortunately, the past 5 years have witnessed remarkable innovations in migraine therapy. Based on a conceptional paradigm shift in migraine research (vascular versus neuronal dysfunction), novel targeted acute and preventive drugs have emerged on the market, including ditans (5-HT1F receptor agonists), gepants (CGRP receptor antagonists), and monoclonal anti-CGRP/receptor antibodies, which have brought new hope to patients [235, 277, 278].
Ditans
In humans the 5-HT1F receptor is expressed in the trigeminovascular system and central nervous system, including the cortex, the hypothalamus, the trigeminal ganglia, the locus coeruleus, the upper cervical cord, and the cerebral blood vessels, as well as in the thyroid and tonsils, kidneys, testes, and ovaries. Its expression in coronary arteries is low, and it is absent in the heart. In all cases the 5-HT1F receptor has no vasoconstrictive properties.
Soon after the discovery of the 5-HT1F receptor in 1993 [279], Eli Lilly started an extensive discovery program for a novel antimigraine compound that selectively addresses this new subtype of serotonin receptors and hopefully thereby lacks any cardiovascular and cerebrovascular effects. Continued research finally yielded a compound LY573144, which proved to have a 450-fold higher affinity at the 5-HT1F receptor than at 5-HT1B and 5-HT1D receptors (Table 4) [235, 280]. The compound was named lasmiditan and gained approval of the US Food and Drug Administration in 2019. As the first member of the “ditans,” lasmiditan is considered as a first-in-class medication [281]. In contrast to serotonin and the triptans the structure of lasmiditan does not feature an indole as its core structure, but a 2-pyridinyl ketone. Some resemblance is found at the salt-bridge-forming amine. Lasmiditan shares a methyl piperidine moiety with naratriptan.
Lasmiditan penetrates the blood–brain barrier and exerts its activity by activating the 5-HT1F receptors, centrally at the trigeminovascular system and peripherally at the trigeminal neurons [235]. The activation of the 5-HT1F receptors inhibits the release of neuropeptides and neurotransmitters such as CGRP and glutamate, which decreases neurogenic inflammation of the dura and ultimately inhibits pain signaling pathways in both the central nervous system and the trigeminovascular system [282, 283].
Gepants and monoclonal antibodies
Chemical syntheses of migraine drugs
The development of modern migraine drugs spans the past 100 years and thus coincides with the era of blossoming medicine and the period of rapidly developing organic chemistry and biochemistry. Both developments were mutually beneficial and an indispensable prerequisite for the synthesis of increasingly selective active substances for the treatment of migraine.
Lysergic acid
Since the 1950s, lysergic acid attracted the attention of numerous researchers in the field of natural product synthesis. To the best of our knowledge, some 20 total syntheses have been published so far. It seems reasonable that almost all syntheses commence with an indole derivative (AB), followed by ring closures of the C and D rings. Until James Hendrickson’s total synthesis in 2004, all approaches targeted the racemic product. In the same year, Csaba Szántay from Budapest University published the first synthesis of (+)-lysergic acid via resolution of an advanced intermediate. The first enantioselective synthesis is attributed to Nobutaka Fujii and Hiroaki Ohno from Kyoto University. Hendrickson’s synthesis is particularly striking because it yields racemic lysergic acid with a 14.5% yield in only nine steps. Unfortunately, according to David E. Nichols [311] and Dale L. Boger [312] this synthesis appears to be controversial. But most recently Joel M. Smith from Florida State University contributed a remarkable concise total synthesis providing racemic lysergic acid in only six steps and 12.0% overall yield. In respect to the number of reaction steps and overall yield, the most efficient total synthesis of (+)-lysergic acid derived from Tohru Fukuyama from Nagoya University in 2013 (Table 7).
Woodward’s total synthesis of racemic lysergic acid
Woodward chose 3-indolylpropionic acid as starting material for his lysergic acid synthesis, though he was fully aware of the high reactivity of the indole compounds that might become an obstacle on later stages. Therefore, he adopted the artifice of reduction at the very beginning to circumvent such problems. Dihydroindole derivatives are much less reactive and more suitable for the envisioned endeavor. After benzoylation of the amino group the tricyclic ketone was obtained by Friedel Crafts acylation in carbon disulfide, while other attempts, such as running the reaction in benzene or applying hydrogen fluoride as Lewis acid, failed. After much experimentation Woodward succeeded introducing methylaminoacetone ethylene ketal directly at position 5, which set the stage for an intramolecular aldol reaction, and providing the desired tetracyclic unsaturated ketone. Subsequent successive treatment with acetic anhydride and sodium borohydride leads to an allylic alcohol, which was converted into the corresponding nitrile. Finally, racemic lysergic acid was obtained by Pinner reaction followed by refluxing in aqueous potassium hydroxide in the presence of sodium-arsenate-deactivated Raney nickel (Scheme 3) [157, 158].
Hendrickson’s total synthesis of racemic lysergic acid
In 2004, James B. Hendrickson (1928–2018) [338] from Brandeis University published the ninth total synthesis of racemic lysergic acid, but the first one entirely avoids protecting group chemistry [326]. To increase step economy, Hendrickson considered the assembly of the framework from readily available indole and nicotinic acid starting materials as the most efficient route and avoided also the initial reduction of the indole, which was frequently performed in previous syntheses (Scheme 4).
The first key step in Hendrickson’s lysergic acid synthesis is a Suzuki coupling of indole-4-boronic acid and 3-chloro-pyridine-2,5-dicarboxylic acid diethyl ester, obtained in few steps from 4-bromoindole and 6-carboxynicotinic acid, respectively. Regioselective reduction of the ester in ortho-position and MnO2 oxidation provides an aldehyde, which, in the presence of a catalytic amount of sodium methanolate, cyclizes readily at room temperature. The alcohol obtained is reduced with borane in THF. The final three steps, comprising pyridine methylation, reduction of the D ring and hydrolyses of the ester are carried through without isolation and purification of the intermediates, finally yielding racemic lysergic acid in nine steps from 4-bromoindole in an overall yield of 14.5%. It should be noted that chirality is introduced only in the final reduction step of the pyridinium salt, which poses a challenging invitation for further improvements (Scheme 5) [339, 340].
Fukuyama’s total synthesis of (+)-lysergic acid
Tohru Fukuyama from Nagoya University published in 2013 an extraordinary, enantioselective total synthesis of (+)-lysergic acid. Key features of the route are the Evans aldol reaction providing the stereogenic centers at the allylic positions, a ring-closing metathesis and an intramolecular Heck reaction to establish the C and D rings [334].
The synthesis commences with two Evans aldol reactions of crotonamide A with TBS-protected hydroxyacetaldehyde and an indole carbaldehyde, respectively. By hydrazinolysis the auxiliary is cleaved off and a Curtius rearrangement provides an isoxazolone. Deoxygenation with triethylsilane, titanium tetrachloride leads to an allylamine, which after reductive amination with the other Evans aldol product B and Boc protection of the amine, sets the basis for intramolecular ring closing metathesis. Stereoselective ring closure of the C ring by a Heck reaction establishes the lysergic acid scaffold. The remaining transformations comprise the degradation of the diol to the carboxylic acid, double bond isomerization, deprotection and methylation of the D ring with formaldehyde sodium cyanoboranate. The longest linear sequence extends to 19 steps and provides (+)-lysergic acid in remarkable 12% overall yield (Scheme 6).
Smith’s total synthesis of racemic lysergic acid
Joel M. Smith’s synthesis of racemic lysergic acid commences with a magnesium–halogen exchange of methyl 6-iodonicotinate followed by a Grignard reaction with 4-bromoindole-3-carboxaldehyde. After reduction of the resulting alcohol and re-protection of the indole, the pyridine moiety is reduced to generate a 1,2-dialkyl-3,6-dihydro-2H-pyridine, which is repetitively subjected to an isomerization process with lithium tetramethylpiperidide to obtain the corresponding 1,6-dialkyl-3,6-dihydro-2H-pyridine isomer. The following Heck annulation with the anti-isomer, employing Gregory Fu’s in situ generated Pd(0) catalyst [341] provided a mixture of stereoisomers of the Boc-protected methyl ester of paspalic acid and lysergic acid. Finally, racemic lysergic acid was afforded from this mixture by saponification and isomerization in an overall yield of 12% (Scheme 7).
Ergotamine
The first synthesis of ergotamine was published by Albert Hofmann in 1961 [151, 342]. Stimulated by Woodward’s total synthesis of lysergic acid, the chemists at Sandoz spent some effort to extend the synthesis to the peptidic part of the molecule. They started from cyclo(l-Phe-l-Pro) ((3S,8aS)-3-benzyl-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione), which was reacted with racemic ethyl 2-benzyloxy-3-chloro-2-methyl-3-oxo-propanoate to obtain already the desired tricyclic scaffold, which is part of ergotamine. After hydrolysis of the ethyl ester, the corresponding acyl azide is synthesized, which by Curtius rearrangement and hydrogenolytic cleavage of the resulting carbamate provides the required amine. Ergotamine is finally obtained by its reaction with lysergic acid chloride. The overall yield amounts to just 10.8%, resulting mainly from the poor yield on the last stage of this route (Scheme 8).
It must be mentioned, however, that notwithstanding of all the achievements in preparative organic chemistry, we have never in history, nor today, been able to provide ergot alkaloids by total synthesis on an economical basis. Industrial extraction began soon after World War I at Sandoz, and Sandoz dominated the production until the 1950s, when other companies started business in the same field, including Boehringer Ingelheim (Germany), Galena (Czech Republic), Gedeon Richter (Hungary), Lek (Slovenia), and Farmitalia (Italy). Nevertheless, still today, Novartis, the successor to Sandoz, retains leadership in world production of ergot alkaloids [142]. The first quantities of ergotamine were produced from ergot sclerotia found in crop fields. When the demand for ergot for extraction exceeded the amount obtained from collection in rye fields, methods for artificial inoculation of rye were developed (Fig. 27).
However, already in 1960, Federico Arcamone (together with Ernst Boris Chain (1906–1979) at the Instituto Superiore di Sanità in Rome demonstrated that simple lysergic acid derivatives could also be produced in high yield by fermentation in submerged culture by a strain of Claviceps paspali, found growing on a hill in the neighborhood of the city [343]. Independently, Sandoz in Basel, Spofa in Prag, and Farmitalia in Milan started research and succeeded soon in manufacturing ergot alkaloids, including ergotamine, with strains of Claviceps purpurea [197, 344,345,346,347,348]. Since the 1990s, it became known that ergot alkaloids can also be produced advantageously by Claviceps fusiformis and Claviceps purpurea in solid-state fermentation [349]. Meanwhile, the main part of production is based on this technology, while field cultivation on triticale [a hybrid of wheat (Triticum) and rye (Secale)] balances the demand. In recent years, the annual production of lysergic acid, mainly used for the manufacturing of semisynthetic derivatives, has been estimated at 15 tons, not including illegal quantities, of course [142].
Triptans
Compared with ergotamine, the triptans are structurally much simpler and can be easily obtained by chemical synthesis [366]. Being indole derivatives, the key step of the first manufacturing processes was a Fischer indole synthesis as one might expect. However, this approach harbored an intrinsic drawback, which also triggered the development of other routes.
Sumatriptan
Glaxo’s sumatriptan [367, 368] synthesis began with the preparation of the hydrazine derivative, required for the Fischer indole synthesis, by hydrogenation of N-methyl-4-nitrobenzenemethanesulfonamide, followed by diazotation and reduction of the diazonium salt with tin chloride. Condensation with 4,4-dimethoxy-N,N-dimethylbutylamine provided a hydrazone that was subjected to the Fischer indole synthesis, applying the Langheld ester (which is an ethyl metaphosphate [369], first prepared from phosphorus pentoxide and diethyl ether by Kurt Langheld at the University Breslau in 1910 [370, 371]) (Scheme 11) [372, 373].
The low yield on the final stage is to some extent related to the formation of side products A and B. Sumatriptan, which also shares this feature with almotriptan [374] and rizatriptan [375], has the structure of a 3,5-dialkylindole with a nucleophilic center at position 2 and an XCH2 group at position 5, where X can act as a leaving group under acid catalysis of conventional Fischer indole reactions (Fig. 29) [376, 377].
In 1999, BASF applied for a patent claiming a highly streamlined and optimized synthesis of sumatriptan, which was developed by researchers at a former Boots site in Nottingham, UK [378]. Hydrogenation of N-methyl-4-nitrobenzenemethanesulfonamide, diazotation, and reduction of the diazonium salt are performed as a one-pot reaction. The use of sodium dithionite rather than stannous chloride was a significant improvement, avoiding toxicological and environmental concerns. In the next step, known as the Grandberg version of the Fischer indole synthesis [379, 380], the hydrazine is condensed with 4-chlorobutanal dimethyl acetal, followed by refluxing of the resulting hydrazone in the presence of disodium hydrogen phosphate, which leads to indolization and displacement of the chloro group with the ammonia released during the formation of the indole ring. The synthesis of sumatriptan is finally completed by reductive amination with aqueous formaldehyde and sodium borohydride (Scheme 12).
Chemists from Gedeon Richter LTD in collaboration with the Technical University of Budapest focused their attention on the low yields of the Fischer indole synthesis and the formation of byproducts. They also merged the synthesis of the hydrazone and Fischer indolization. However, they chose a protected sulfonamide, and by that they were able to avoid byproduct A, but not the formation of impurity B (Scheme 13) [381].
Consequently, they also investigated the Japp–Klingemann approach, which comprises the reaction of the diazonium salt with ethyl 2-(3-dimethylaminopropyl)-3-oxobutanoate and Fischer cyclization. Due to protection at position 2 and at the sulfonamide the resulting indole is not prone to subsequent reactions, which avoids byproducts A and B and increases yield. After hydrolysis of the esters and decarboxylation, sumatriptan was obtained in improved overall yield (Scheme 14) [382].
Zolmitriptan
Zolmitriptan was discovered by Burroughs Wellcome in the UK in 1990 [383], but upon acquisition of Wellcome by Glaxo, the intellectual property was transferred to Zeneca [384]. In the first part of the synthesis an oxazolidinone is prepared starting from 4-nitro-l-phenylalanine, in which the latter is converted into the methylester, reduced with sodium borohydride, and reacted with phosgene. Hydrogenation, diazotation, and reduction with stannous chloride provided a hydrazine that is subjected to a Grandberg–Fischer indole synthesis. Finally, dimethylation by reductive amination afforded zolmitriptan (Scheme 15).
The inventors of this synthesis succeeded in dramatically improving the Fischer indole synthesis by using 3-cyanopropanaldiethyl acetal, but they then lost most of the material in the final reductive transamination (Scheme 16) [384].
In 1995, however, Rajnikant Patel at Zeneca filed a remarkable patent for an elegant, large-scale, so-called one-pot synthesis of zolmitriptan that left all these hurdles and drawbacks behind [385]. The synthesis commenced by reacting methyl 4-nitro-(l)-phenylalanine with n-butyl chloroformate. The resulting butyl carbamate is subjected directly to hydrogenation of the nitro group. After solvent swap to butanol, the methyl ester is reduced with sodium borohydride and treatment with sodium methoxide leads to the oxazolidinone, which, after crystallization, is isolated as a solid. Diazotation and reduction of the diazonium salt with aqueous sodium sulfite provides the corresponding hydrazine. Addition of 4,4-diethoxy-N,N-dimethylbutylamine and boiling to reflux for several hours provide crude zolmitriptan, which is purified be recrystallization. Unfortunately, Zeneca was reluctant to provide the exact total yield, but indicated that it was high. Matrix Laboratories later described an analogous synthesis of N-desmethyl zolmitriptan with a yield of 60% (Scheme 17) [386].
Naratriptan
Naratriptan was a follow-up compound to sumatriptan, discovered at Glaxo in 1987 [387]. The synthesis started with 5-bromoindole, which was condensed with N-methyl-4-piperidone, followed by hydrogenation of the resulting enamine. Heck reaction with N-methylvinylsulfonamide and hydrogenation afforded naratriptan in 25.3% overall yield (Scheme 18).
More recently, Glaxo detailed a process for the manufacturing of naratriptan on kilogram scale [388]. The synthesis is very similar to their original route. However, the hydrogenation steps were combined, and the others optimized leading to an efficient approach with an overall yield of 75.3% (Scheme 19).
Almotriptan
Almotriptan was discovered and developed at Almirall, but later also licensed to Pharmacia and Janssen [374]. Initially, it was prepared by the Grandberg modification of the Fischer indolization, but more recent approaches involve also Pd-catalyzed coupling reactions, such as the intramolecular Heck reaction [389] or the Negishi reaction [390].
The precursor for the Heck reaction is obtained by iodation of an appropriately decorated aniline, followed by protection and alkylation with methyl 4-bromocrotonate. The key step of this route comprises a palladium-catalyzed Heck cyclization with concomitant deprotection of the indoleacetic methyl ester. Almotriptan is obtained via the N,N-dimethyl carboxamide, which is reduced applying lithium aluminum hydride (Scheme 20).
The starting material for the Negishi reaction is synthesized from commercially available 5-bromoindole, which is reacted with oxalyl chloride and gaseous dimethylamine, followed by reduction with lithium aluminum hydride and Boc-protection. The Negishi reaction with 1-(methylsulfonyl)pyrrolidine proceeds at 65 °C and affords the desired product in 86% yield. Deprotection finally provided almotriptan in high purity (Scheme 21).
Frovatriptan
Frovatriptan was discovered in the early 1990s at SmithKline Beecham [391, 392], but licensed to Vanguard Medica/Vernalis for development. Its structure is similar to Glaxo’s development substance AH21467, however bearing a conformationally restrained cyclohexane, which is condensed to the indole at position 2 and 3. Frovatriptan can be synthesized via Fischer indole synthesis. In a highly convergent synthesis, the building block A, obtained by reductive amination of the mono-ketal of 1,4-cyclohexanedione, is reacted in a one-pot reaction with a hydrazine synthesized from 4-aminobenzamide, to produce racemic frovatriptan in an overall yield of 63%. The enantiomers can be separated by crystallization with di-p-toluoyl-(d)-(+)-tartaric acid (Scheme 22) [393].
Eletriptan
Pfizer also joined the race for new triptans, leading to the discovery of eletriptan in the 1990s [394]. The first manufacturing process commenced from 5-bromoindole, which was condensed with (R)-N-methyl proline chloride. After reduction of the resulting ketone with lithium aluminum hydride, the indole is protected, and the vinyl sulfone introduced in position 5 by a Heck-type reaction. The final steps of the synthesis of enantiopure eletriptan comprise the hydrogenation of the double bond, deprotection, and salt formation (Scheme 23) [395].
The process proved to be well developed and robust but suffered nevertheless from some shortcomings related to the use of the costly (R)-proline derivative, the lithium aluminum hydride reduction, generating large waste streams and the highly noxious and sensitizing reagent phenyl vinyl sulfone. These were sound reasons for Pfizer to search for a better synthesis.
Like many other companies, they chose to center their new approach on Fischer indole chemistry, which was considered a well-researched and highly reliable conversion that should deliver eletriptan in a convergent and highly efficient way. Unexpectedly, however, the first attempts to synthesize eletriptan by this route failed, which was attributed to the instability of the hydrazine under the relatively harsh reaction conditions. Nevertheless, the problem could be solved soon (Scheme 24) [396, 397].
Starting from 4-methylaminobutyric acid, this is first converted into the N-protected Weinreb amide and subsequently into a ketone by a Grignard reaction. Hydrogenation furnishes the desired pyrrolidine, which is crystallized as a fumarate salt. The required aniline is obtained from 1-(2-bromoethyl)-4-nitrobenzene by nucleophilic substitution with sodium benzene sulfinate and hydrogenation of the nitro group. Most remarkable, however, is the ending of the synthesis. Pfizer managed to run the remaining steps, i.e., the diazotation of the aniline, the reduction of the diazonium salt, and the Fischer indole reaction under very mild conditions as a one-pot reaction, using ascorbic acid as reducing agent of the diazonium salt. Moreover, the use of ascorbic acid is advantageous, because vitamin C is inexpensive, nontoxic, and environmentally benign (Scheme 25).
The proposed mechanism for the diazonium salt reduction is an electrophilic attack of the diazonium group at position 3 of ascorbic acid, followed by a hetero-ene-like breakdown process of the hemiacetal, leading to a protected hydrazine A, which can be isolated as calcium salt. In the subsequent indole synthesis, a certain analogy to the Japp–Klingemann reaction can be noticed (Scheme 26) [398].
The utilization of enantiopure pyrrolidine in this process, which can be readily obtained from the racemate by crystallization with dibenzoyl-l-tartaric acid, also provides access to enantiopure (R)-eletriptan (Scheme 27).
Lasmiditan
The synthesis of lasmiditan by Eli Lilly is mainly based on three building blocks: piperidine-4-carboxylic acid, 2,6-dibromopyridine, and 2,4,6-trifluoro-benzoyl chloride [427, 428]. It starts with piperidine-4-carboxylic acid, which after reductive amination is reacted with dimethylamine to give the corresponding dimethylamide. In the following reaction steps, the two bromine substituents of 2,6-dibromopyridine are replaced by this amide and ammonia, respectively, prior to the final amide formation with 2,4,6-trifluoro benzoyl chloride, eventually leading to lasmiditan in 90% overall yield. More recently other companies have claimed similar processes (Scheme 28) [429, 430]
Gepants
Ubrogepant
Once ubrogepant was identified as a new CGRP receptor antagonist and underwent further clinical trials, Merck also started process development for the manufacturing of this compound [431]. Retrosynthetic considerations indicated that ubrogepant should be readily prepared by amide formation from spiro acid A and lactam B; however, the real challenge would reside in the preparation of these building blocks. In case of the spiro acid A the task centered around the enantioselective spirocyclization potentially starting from two different key intermediates C or D, to establish the chiral all-carbon quaternary stereocenter.
Even more challenging might be the synthesis of lactam B with three chiral centers. The chemists at Merck decided to evaluate enzymatic dynamic kinetic transamination as a method setting the two stereocenters in position 5 and 6 and lactam formation simultaneously. After N-alkylation they expected performing a diastereomeric transformation of the stereocenter at position 3, thermodynamically driven by crystallization of an appropriate salt (Fig. 31).
In advance to the process development of spiro acid A, the chemists at Merck investigated the two alternative spirocyclization reactions starting from model substances C and D (R = Br). While cyclization of D under phase transfer conditions proceeded smoothly, they encountered substantial problems starting from C. This was a guiding result and shaped the way forward. Accordingly, 2,3-dibromo-5-chloropyridine was selected as the starting material. Regioselective transmetalation, followed by quenching with DMF and reduction provided an alcohol, which after protection as THP ether was subjected to a second formylation. Aldol condensation with 1 N-t-butyl-7-azaindol-2-one resulted in a highly crystalline, Z-configurated α,β-unsaturated ketone. In the following steps the alkene is reduced with sodium borohydride, the THP ether is cleaved, and the resulting alcohol is replaced by chlorine to set stage for enantioselective spirocyclization. In the course of screening a library of chiral phase transfer catalysts, a novel N,N′-doubly quaternized PTC was discovered serendipitously, which turned out as the most selective and potent catalyst of the collection [432]. At the climax of the synthesis of spiro acid A, the desired compound was obtained by Pd-catalyzed carbonylation and acidic N-deprotection (Scheme 29).
Starting material for lactam B was N-Boc-serine isopropyl ester, which was first turned to the dehydroalanine derivative by mesylation and elimination, and then condensed with 4-bromophenylacetone [433]. Debromination by transfer hydrogenation with potassium formate provided the intermediate for enzymatic transamination. In the course of a screening program, a transaminase panel from Codexis was searched for activity, followed by protein engineering to enhance solvent tolerance and temperature stability of the enzymes. The outcome was a pyridoxyl phosphate-dependent transaminase, which provided the desired lactam in 92% yield, with > 99% ee at C-6 and a 61: 1 syn/anti ratio at C5/C6. The crystalline product turned out as a 3: 2 mixture of diastereomers, in respect to stereocenter 3, which, however, is prone to epimerization, especially under basic conditions, required for the following alkylation. The conditions, therefore, had to be chosen very carefully, due to a second alkylation at the Boc-protected amino group before complete consumption of the non-alkylated lactam. However, after Boc deprotection and salt formation, the amino lactam was recovered as 4: 1 mixture in favor to the desired diastereomer. In a salt screening p-toluic acid turned out superior for the 3,5-dichloro salicylaldehyde-catalyzed dynamic kinetic resolution of the diastereomers by crystallization to finally furnish the lactam B salt in 86% yield and 99.6% de (Scheme 30).
With both building blocks in hand on 100 kg scale, the stage was set for the final coupling reaction and the isolation of ubrogepant. The amide formation was performed in aqueous acetonitrile solution with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide as coupling agent and a catalytical amount of 2-hydroxypyridine N-oxide, without epimerization at position 3. Ubrogepant was finally isolated as trihydrate by crystallization from aqueous ethanol with 95% yield and excellent optical and chemical purities (Scheme 31).
Rimegepant
Bristol-Myers Squibb’s CGRP antagonist rimegepant can be split retrosynthetically at the central carbamate into a 1,3,7-triazaindan-2-one derivative and a remarkable cycloheptanol with three stereocenters, and indeed, the active ingredient is synthesized from these building blocks in a highly convergent approach (Fig. 32).
While a few distinct routes towards the triazaindanone were already known from literature, BMS developed two complementary syntheses, mainly to mitigate raw material costs and to increase reaction efficiency [434].
2-Chloro-3-aminopyridine, a readily available and inexpensive bulk chemical, can be subjected to reductive amination with 1-Boc-4-piperidone and sodium triacetoxy boranate. As it turned out, a prerequisite for high selectivity and yield is the use of trifluoroacetic acid, which ensures complete conversion of the starting material with minimal direct reduction of the piperidone. Subsequently, the chloro substituent is replaced by an amino group by Pd-catalyzed amination. Benzophenone imine was used for its bulkiness as an ammonia surrogate, to minimize formation of a byproduct, followed by addition of citric acid, to cleave the resulting N-hetarylated benzophenone imine without affecting the Boc protecting group.
The same intermediate can be obtained by reductive amination starting from 2,3-diaminopyridine. Once again, the use of trifluoroacetic acid proved advantageous in minimizing double alkylation.
Finally, the desired building block for rimegepant was obtained, by reacting the intermediate with carbonyl diimidazole and removal of the Boc protecting group with ethanolic HCl (Scheme 32).
The starting material for the second building block, the cycloheptanol derivative, can be synthesized via classical Dieckmann condensation of dimethyl pyridine-2,3-dicarboxylate and dimethyl glutarate followed by hydrolysis and decarboxylation (Scheme 33) [435].
For regio- and enantioselective reduction of 7,8-dihydro-6H-cyclohepta[b]-pyridine-5,9-dione, the chemists at BMS, first considered an enzymatic approach, of course; however, they later found superior regio- and enantioselectivity with Rh(R-binapine)(COD)BF4, a highly active transition metal catalyst [436]. After protection of the alcohol with the bulky triisopropylsilyl group, the next steps targeted Pd-catalyzed α-arylation of the ketone. Being fully aware that stereoselectivity of the C–C-bond formation would be limited, there was some hope taking advantage of the readily epimerizable nature of the newly formed stereocenter. Under optimized conditions the α-arylation provided a 12 : 1 mixture of diastereomers. Subsequent epimerization with DBU led to the desired product in 57% yield with a ratio of diastereomers of 40: 1.
After diastereoselective reduction of the ketone using lithium tri-t-butoxyaluminum hydride, a double inversion strategy was used to turn the resulting alcohol into the corresponding azide preserving the absolute configuration [437].
Removal of the silyl protecting group set the stage for the coupling reaction with the carbamate of the triazaindanone with sodium hexamethyldisilazide at −15 °C and rimegepant is obtained finally by reduction of the azide with trimethylphosphane (Scheme 34) [438, 439].
Atogepant
Atogepant, also discovered at Merck, is a close analog of ubrogepant, which has just three additional fluoro substituents on lactam B. Accordingly, the technical synthesis might be the same or at least very similar. Notwithstanding this, another approach will be briefly considered below (Fig. 33) [440, 441].
Here, starting material for the spiro acid A is pyridine-2,3-dicarboxylic acid, which after esterification is brominated at position 5. Reduction of both methyl esters and mesylation provides the intermediate ready for spirocyclization with 2-(trimethylsilyl)ethoxymethyl-protected azaindolone. The spiro compound is subjected to carbonylation with subsequent esterification. Following separation of the enantiomers by chiral column chromatography, the desired (S)-enantiomer is then subjected to N-deprotection with HCl and hydrolysis of the ester (Scheme 35).
The lactam B′ can be synthesized starting from 5-bromo-6-methylpyridin-2-ol, which after N-alkylation with 2,2,2-trifluoroethyl triflate is subjected to a Suzuki coupling to introduce the trifluorophenyl rest and subsequently to hydrogenation. The resulting lactam is then treated with sodium hexamethyldisilazide and 2,4,6-triisopropylbenzenesulfonyl azide for electrophilic transfer of an azide group. Simultaneous hydrogenation and Boc protection provide a mixture of stereoisomers, which can be separated by chiral supercritical fluid chromatography (SFC). The desired enantiomer is deprotected and finally coupled with the spiro acid A to give atogepant (Scheme 36).
Zavegepant
A second CGRP receptor antagonist discovered and developed at Bristol-Myers Squibb is zavegepant. As shown in the retrosynthetic analysis, the molecule consists of three fragments, which are connected via amide bonds. Since the piperazine building block (blue) is commercially available, the process development focused on the synthesis of the quinolone (red), the enantiopure amino acid (black), and of course the assembly of the final product (Fig. 34) [442].
The first step towards the quinolone is a Horner–Wadsworth–Emmons reaction of N-Boc-4-piperidone with trimethylphosphonoacetate. The α,β-unsaturated ester is hydrogenated and subjected to an aldol reaction with o-nitro benzaldehyde. Reduction of the nitro group with iron in acetic acid, cyclization, and elimination of water affords 3-(4-piperidyl)-1H-quinolin-2-one (Scheme 37) [443].
For the synthesis of the chiral amino acid of zavegepant, the discovery chemists at BMS borrowed conceptually from the classical synthesis of Monsanto’s Parkinson’s drug (l)-3,4-dihydroxyphenylalanine by rhodium-catalyzed enantioselective hydrogenation [444]. They synthesized the precursor, the amino cinnamic acid, by Heck cross coupling from an appropriately decorated aryl iodide and amino acrylate (Fig. 35).
Like the synthesis of ubrogepant, the aminoacrylate is available from serine methyl ester by N-protection under Schotten–Baumann conditions, mesylation, and elimination. When it became apparent that the isolated acrylate tended to polymerize, isolation was abandoned, and the substance was only handled in solution (Scheme 38).
In the original route of discovery chemistry at BMS 2,6-dimethylaniline was iodated using iodine monochloride. After the Heck reaction, enantioselective hydrogenation was performed applying an enantiopure Et-DuPHOS-Rh catalyst to obtain the corresponding amino acid in excellent selectivity and yield. The indazole was established by nitrosation of one of the methyl groups with isoamyl nitrite and spontaneous dehydration. Finally, the Cbz-protecting group was removed by hydrogenation (Scheme 39).
The process development chemists at BMS adopted this route in their first approach, but addressed several significant issues prior to scale-up. One of these problems was the color of the iodoaniline, which persisted into the product of the Heck reaction. The issue was solved by replacing ICl with commercially available benzyltrimethylammonium dichloroiodate, which afforded the aniline hydrochloride salt as an off-white solid. The Heck reaction worked smoothly, and the product was purified by crystallization of the mesylate. However, in the following enantioselective hydrogenation with the Et-DuPHOS-Rh catalyst, the reaction rate was low and limited catalyst stability necessitated high catalyst loading. Therefore, it was replaced with a more active and robust Et-FerroTANE-Rh catalyst. While the nitrosation went without a hitch, deprotection of the Cbz group by hydrogenolysis unexpectedly became a source of considerable trouble. Under the bottom line it was related to the inevitable liberation of carbon dioxide, which formed a carbonate or carbamate precipitate of the amino ester, preventing the clean separation of the solid Pd/C catalyst. The problem was ultimately solved by purging the reaction mixture after hydrogenation with nitrogen and HCl salt formation in course of the work-up (Scheme 40).
Aside from this enantioselective, transition metal catalysis-based approach, the development chemists investigated also a conceptional different enzymatic synthesis. It was expected that, unlike the metal catalyst hydrogenation, the indazole functionality should be compatible with the biocatalytic transformation. That would allow the preparation of the heterocycle right at the beginning of the synthesis, while the introduction of chirality could be shifted to the penultimate step. Thus, the primary goal of the chemical synthesis was an α-keto carboxylic acid, which subsequently would be converted into the (R)-amino acid by a d-transaminase.
The synthesis commences with commercially available 4-bromo-2,6-dimethylaniline, which is reacted with t-butyl nitrite similar to previous synthesis to give rise of the corresponding indazole. In the following step, the indazole is deprotonated with nBuLi prior to the lithium/bromine exchange with secBuLi, to avoid debromination. By DMF quench a carbaldehyde is obtained, which was next subjected to an Erlenmeyer–Plöchl reaction with hippuric acid. Methanolysis of the azlactone was performed with a catalytic amount of NaOMe in methanol. The hydrolysis with aqueous HCl provided the substrate for the enzymatic step.
For the first transamination runs a commercially available d-transaminase from Codexis and racemic alanine as nitrogen source was used. Later BMS discovered a d-transaminase from the soil bacterium Bacillus thuringiensis, which proved to be much more robust and active.
Finally, the amino acid should be turned into the methyl ester, which was hampered by concomitant methylation of the indazole. Only very careful tuning of the reaction conditions with respect to the acetyl chloride equivalents used, the concentration and the temperature applied, and finally the purification of the product by crystallization brought the hoped-for success (Scheme 41).
However, the most challenging part of the synthesis was still ahead, the assembly of zavegepant from the different building blocks by two coupling steps. In particular, the coupling of the quinolone and the amino ester with carbonyl diimidazole proved sensitive to reaction conditions and stoichiometry. It took much effort and diligence to minimize the side-products, which mainly resulted by inadvertent additional coupling reactions. Fortunately, after hydrolysis of the methyl ester, the final amide formation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide furnished the desired product in excellent yield and perfect enantiopurity (Scheme 42).
Migraine and natural medicine
In addition to the above-mentioned migraine treatment options based on synthetic and FDA-approved drugs, there is a plethora of remedies derived from herbal medicines as well as traditional and empirical medicine and dietary supplements. The following list of therapies is far from comprehensive but merely highlights a few examples for which there is a range of scientific studies available [445].
Butterbur root extract
Butterbur (Petasites hybridus) leaves have been used over centuries in Austrian and Czech traditional medicine for the treatment of infections, fever, flu, colds, hay fever, and allergies (Fig. 36) [446]. The extracts of its rhizomes have also been used for the prophylactic treatment of migraine for many years. In a recent study, it had been shown that pre-incubation of rat and mouse cranial dura mater and trigeminal ganglion neurons with the extract’s active ingredients petasin and isopetasin reduced mustard oil- and capsaicin-evoked CGRP release compared with vehicle in an approximately dose-dependent manner [447]. Furthermore, in ex vivo models, the sesquiterpenes petasin and isopetasin have also been found to affect transient receptor potential ankyrin type 1 (TRPA1) and transient receptor potential vanilloid type 1 (TRPV1) receptor channels, leading to a reduction in CGRP levels. However, it remains to be demonstrated whether transient potential melastatin type 8 (TRPM8) receptor channels are affected in a similar manner. This is of considerable interest because it may offer novel approaches for the treatment of migraine.
Riboflavin
Riboflavin (vitamin B2) has been considered effective for the prophylactic treatment of migraine in pediatric, adolescent, and adult patients. Meanwhile, there are numerous small studies demonstrating that riboflavin reduces the frequency of migraine attacks at all ages. Riboflavin is well tolerated even at high doses. However, more data are needed particularly in respect to pharmacokinetics and pharmacogenomics to refine its position in future migraine therapy (Fig. 37) [448].
Melatonin
Melatonin is a hormone, released by the pineal gland in the brain, that is critical for the control of the sleep–wake cycle. It may also play a role in the pathophysiology of migraines by activating melatonin receptors in the hypothalamus [452]. Meanwhile, several studies have been published demonstrating that melatonin is effective in children and adolescent patients. In a 3-month trial in children with migraines, it was shown that melatonin significantly decreases the frequency and duration of headache attacks and disability levels [453]. There is much hope that melatonin might become an alternative in migraine prophylaxis, but more research is required, e.g., in terms of pharmacology and safety (Fig. 38) [454].
Coenzyme Q 10
Coenzyme Q10 is an electron carrier in the mitochondrial electron transport chain and therefore essential for all energy related cellular processes. The observation that mitochondrial energy is depleted in brain tissues of migraine patients without aura supported the hypothesis that supplementation with coenzyme Q10 might be beneficial preventing migraines [456, 457]. While a trial in children and adolescents in 2011 was not convincing [458], a meta-analysis of trials in adult patients shows that coenzyme Q10 supplementation reduces both the frequency and duration of migraine attacks, but not their severity compared with the control group (Fig. 39) [459].
Magnesium
The availability of magnesium salts is crucial for many physiological processes in the brain associated with the pathophysiology of migraine. Since the 1990s, there is a growing body of evidence that magnesium deficiency may contribute to migraine development [463, 464]. Magnesium deficiency affects mitochondrial metabolism, which could alter neuronal polarization and may result in cortical spreading depression [465]. Migraine attacks are usually accompanied by low magnesium concentrations in serum and cerebrospinal fluid [466]. The underlying cause of hypomagnesemia in patients with migraine is unknown, but may be due to inadequate uptake, excessive loss of magnesium in the urine, genetic disposition, or some combination thereof. By now, several intervention trials in children, adolescents and adults have been performed. Unfortunately, the strength of evidence supporting oral magnesium supplementation is still limited [467]. But most recently there are some promising studies indicating that supplementary magnesium might be beneficial, especially in pediatric but also in adult patients [468,469,470].
References
https://www.scottishpoetrylibrary.org.uk/poet/william-dunbar/ (retrieved 25 May 2021)
Buchanan WW, Upton ARM (2005) J R Coll Physicians Edinb 35:371–337
https://en.wikipedia.org/wiki/On_His_Heid-Ake (retrieved 25 May 2021)
Migraines were taken more seriously in medieval times – where did we go wrong? (theconversation.com) (retrieved 25 May 2021)
https://americanmigrainefoundation.org/resource-library/timeline-migraine-attack/ (retrieved 1 June 2021)
https://oldweirdscotland.com/tag/makar/ (retrieved 1 November 2022)
https://theconversation.com/drilling-holes-in-the-skull-was-never-a-migraine-cure-heres-why-it-was-long-thought-to-be-90782 (retrieved 30 May 2021)
Popko L (2018) Bull Hist Med 92:352–366
Edmeads J (1999) Can J Clin Pharmacol 6:5A-8A
Magiorkinis E, Diamantis A, Mitsikostas DD (2009) Androutsos. J Neurol 256:1215–1220
Assina R, Sarris CE, Mammis A (2014) Neurosurg Focus 36:1–6
Greenberg D, Aminoff M, Simon R (2018) Clinical Neurology, Chapter 6, Headache & Facial Pain, 10th edition, McGraw Hill Professional
Hippocrates (1846) The seventh book of epidemics. In: Redman Coxe J (ed) The writings of Hippocrates and Galen. Epitomised from the original Latin translations. Lindsay and Blakiston, Philadelphia. The Writings of Hippocrates and Galen | Online Library of Liberty (libertyfund.org) (retrieved 30 May 2021)
Sabatowski R, Schäfer D, Brunsch H, Radbruch L, Kasper S (2004) Curr Pharm Des 10:701–716
Tao H, Wang T, Dong X, Guo Q, Xu H, Wan Q (2018). J Headache Pain. https://doi.org/10.1186/s10194-018-0868-9
Moisset X, Pereira B, Ciampi de Andrade D, Fontaine D, Lantéri-Minet M, Mawet J (2020) The Journal of Headache and Pain. https://doi.org/10.1186/s10194-020-01204-4
Drabkin IE (1950) Scotomia description. Caelius Aurelianus on acute diseases and on chronic diseases. University of Chicago Press, Chicago, pp 472–473
Diamond S, Franklin MA (2005) Headache through the ages. Professional Communications Inc, Caddo, pp 34–50
https://books.google.de/books?id=CGdZfKPSjSMC&printsec=frontcover&hl=de#v=onepage&q&f=false (retrieved 8 June 2021)
Isler H (1986) Headache 26:95–98
Latham PW (1873) On nervous or sick-headache, its varieties and treatment, Cambridge, Deighton, Bell & Co
Latham PW (1873) Br Med J I:113–114
Weatherall MW (2012) Brain 135:2560–2568
Liveing E (1873) Pathology of megrim and allied disorders. In: On Megrim and Sick-Headache and some allied disorders: a contribution to the pathology of nerve storms, chap V. Churchill, London, 335–398
Gowers WR (1888) A manual of diseases of the nervous system, vol 2, J&A Churchill, London, 793 https://wellcomecollection.org/works/wbnkmjub/items?canvas=9, (retrieved 8 June 2021)
50 Famous People With Migraine – MigrainePal (retrieved 13 June 2021)
Göbel H, Isler H, Hasenfratz HP (1995) Cephalalgia 15:180–181
Jones JM (1999) Cephalalgia 19:627–630
Foxhall K (2014) Med Hist 58:354–374
Singer C (1917) Studies in the History and Method of Science. Oxford, Clarendon Press 1917:1–55
https://www.dsl.ac.uk/entry/dost/magrame (retrieved 5 September 2021)
Airy GB (1865) Phil Mag 30:19–21
Göbel CH, Göbel A, Göbel H (2013). BMJ. https://doi.org/10.1136/bmj.f6952
Göbel A, Göbel CH, Göbel H (2014) Cephalalgia 34:1004–1011
https://www.creativindie.com/diagnosing-dickinson-epilepsy-or-migraine-how-headaches-inspire-artists-and-writers/ (retrieved 13 June 2021)
Podoll K, Robinson D (1999) Lancet 353:1366–1366
Podoll K, Robinson D (2008) Migraine art – the migraine experience from within. North Atlantic Books, Berkeley
Haan J, Ferrari MD (2000) Cephalalgia 20:254–254
Critchley EM (1996) J Neurol. Neurosurg Psychiatry 60:338–338. https://doi.org/10.1136/jnnp.60.3.338
Chirchiglia D, Chirchiglia P, Marotta R (2018). Front Neurol. https://doi.org/10.3389/fneur.2018.00553
Podoll K, Robinson D, Nicolla U (2001) Neurol Psychiatry Brain Res 9:139–156
Blau JN (2004) Cephalalgia 24:215–222
Rose FC (2006) J Headache Pain 7:109–115
Diamond S, Cady RK, Diamond ML, Green MW, Martin VT (Eds) (2015) Headache and migraine biology and management. Elsevier, Oxford, 2015, 1-12
Macgregor EA (2013) Cephalagia 33:951–953
https://www.theguardian.com/uk/2002/feb/09/princessmargaret.monarchy (retrieved 15 December 2021)
Airy H (1870) Philos Trans R Soc London 160:247–264
Eadie MJ (2009) J R Coll Physicians Edinb 39:263–267
https://www.youtube.com/watch?v=Mg1z9RoZR50 (retrieved 19 June 2021)
Todd J (1955) Can Med Assoc J 73:701–704
https://en.wikipedia.org/wiki/Alice_in_Wonderland_syndrome (retrieved 13 June 2021)
International Headache Society (2018) Cephalalgia 38:1–211
https://en.wikipedia.org/wiki/Headache (retrieved 27 June 2021)
Stovner LJ (2018) Lancet Neurol 17:954–976
Safiria S, Pourfathi H, Arielle Eagan A, Mansournia MA, Khodayari MT, Sullman MJM, Kaufman J, Collins G, Dai H, Bragazzi NL, Kolahi AA (2021). Pain. https://doi.org/10.1097/j.pain.0000000000002275
Ashina M, Katsarava Z, Do TP, Buse DC, Pozo-Rosich P, Özge A, Krymchantowski AV, Lebedeva ER, Ravishankar K, Yu S, Sacco S, Ashina S, Younis S, Steiner TJ, Lipton RB (2021) Lancet 397:1485–1495
Hershey AD (2010) Lancet Neurol 9:190–204
https://migraineresearchfoundation.org/about-migraine/migraine-facts/ (retrieved 19 September 2021)
Vo P, Paris N, Bilitou A, Valena T, Fang J, Naujoks C, Cameron A (2018) de Reydet de Vulpillieres F, Cadiou F. Neurol Ther 7:321–332
https://www.novartis.com/news/media-releases/novartis-international-ag-global-study-novartis-and-european-migraine-and-headache-alliance-reveals-60-employed-people-severe-migraine-miss-average-week-work (retrieved 19 September 2021)
https://en.wikipedia.org/wiki/Migraine (retrieved 4 July 2021)
Halpern AL, Silberstein SD (2005). Chapter 9: The Migraine Attack - A Clinical Description, In Kaplan PW, Fisher RS (eds.). Imitators of Epilepsy (2 ed.). New York: Demos Medical. ISBN 978–1–888799–83–5
Amiri P, Kazeminasab S, Nejadghaderi SA, Mohammadinasab R, Pourfathi H, Araj-Khodaei M, Sullman MJM, Kolahi A-A and Safiri S (2022) Front. Neurol. 12. https://doi.org/10.3389/fneur.2021.800605
Levy D, Strassman AM, Burstein R (2009) Headache 49:953–957
Finocchi C, Sivori G (2012) Neurol Sci 33(Suppl 1):S77–S80
Rockett FC, de Oliveira VR, Castro K, Chaves ML, Perla A, Perry ID (2012) Nutr Rev 70:337–356
Freeman M (2006) J Am Acad Nurse Pract 18:482–486
Peterlin BL, Katsnelson MJ, Calhoun AH (2009) Curr Pain Headache Rep 13:404–412
Radat F (2013) Rev Neurol 169:406–412
Chai NC, Peterlin BL, Calhoun AH (2014) Curr Opin Neurol 27:315–324
Schürks M (2012) J Headache Pain 13:1–9
Piane M, Lulli P, Farinelli I, Simeoni S, De Filippis S, Patacchioli FR, Martelletti P (2007) J Headache Pain 8:334–339
Ducros A (2013) Rev Neurol 169:360–371
Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E (1996) Nature 383:707–710
Dussor G, Cao YQ (2016) Headache 56:1406–1417
Zhao H, Eising E, de Vries B, Vijfhuizen LS (2016) International Headache Genetics Consortium, Anttila V, Winsvold BS, Kurth T, Stefansson H, Kallela M, Malik R, Stam AH, Ikram MA, Ligthart L, Freilinger T, Alexander M, Müller-Myhsok B, Schreiber S, Meitinger T, Aromas A, Eriksson JG, Boomsma DI, van Duijn CM, Zwart JA, Quaye L, Kubisch C, Dichgans M, Wessman M, Stefansson K, Chasman DI, Palotie A, Martin NG, Montgomery GW, Ferrari MD, Terwindt GM, van den Maagdenberg AM, Nyholt DR. Cephalalgia 36:648–657
Isler H (1992) J Hist Neurosci 1:227–233
Akkermans R (2015) Lancet 14:982–983
Hausman L (1962) Bull N Y Acad Med 38:826–829
Tfelt-Hansen PC, Koehler PJ (2008) Cephalalgia 28:877–886
Kallela M, Färkkilä M, Saijonmaa O, Fyhrquist F (1998) Cephalalgia 18:329–332
Wolff HG (1963) Headache and other head pains, 2nd edn. Oxford University Press, New York
Ahn AH (2010) Headache 50:1507–1510
Mason BN, Russo AF (2018). Front Cell Neurosci. https://doi.org/10.3389/fncel.2018.00233
May A, Goadsby PJ (1999) J Cereb Blood Flow Metab 19:115–127
Cutrer FM, Charles A (2008) Headache 48:1411–1414
Goadsby PJ (2009) Brain 132:6–7
Lashley KS (1941) Arch Neurol Psychiatry 46:331–339
Leao AA (1944) J Neurophysiol 7:359–390
Ayata C, Lauritzen M (2015) Physiol Rev 95:953–993
Milner PM (1958) Electroencephalogr Clin Neurophysiol 10:705–705
Hoffmann J, Baca SM, Akerman S (2019) J Cereb Blood Flow Metab 39:573–594
Dodick DW (2018) Headache 58:4–16
Richter F, Lehmenkühler A (2008) Schmerz 22:544–550
Dreier JP, Fabricius M, Ayata C, Sakowitz OW, Shuttleworth CW, Dohmen C, Graf R, Vajkoczy P, Helbok R, Suzuki M, Schiefecker AJ, Major S, Winkler MK, Kang EJ, Milakara D, Oliveira-Ferreira AI, Reiffurth C, Revankar GS, Sugimoto K, Dengler NF, Hecht N, Foreman B, Feyen B, Kondziella D, Friberg CK, Piilgaard H, Rosenthal ES, Westover MB, Maslarova A, Santos E, Hertle D, Sánchez-Porras R, Jewell SL, Balança B, Platz J, Hinzman JM, Lückl J, Schoknecht K, Schöll M, Drenckhahn C, Feuerstein D, Eriksen N, Horst V, Bretz JS, Jahnke P, Scheel M, Bohner G, Rostrup E, Pakkenberg B, Heinemann U, Claassen J, Carlson AP, Kowoll CM, Lublinsky S, Chassidim Y, Shelef I, Friedman A, Brinker G, Reiner M, Kirov SA, Andrew RD, Farkas E, Güresir E, Vatter H, Chung LS, Brennan KC, Lieutaud T, Marinesco S, Maas AI, Sahuquillo J, Dahlem MA, Richter F, Herreras O, Boutelle MG, Okonkwo DO, Bullock MR, Witte OW, Martus P, van den Maagdenberg AM, Ferrari MD, Dijkhuizen RM, Shutter LA, Andaluz N, Schulte AP, MacVicar B, Watanabe T, Woitzik J, Lauritzen M, Strong AJ, Hartings JA (2017) J Cereb Blood Flow Metab 37:1595–1625
Géraud G, Denuelle M, Fabre N, Payoux P, Chollet F (2005) Rev Neurol (Paris) 161:666–670
Rustichelli C, Castro FL, Baraldi C, Ferrari A (2020) Expert Opin Investig Drugs 29:1269–1275
Chen ST, Wu JW (2020) Prog Brain Res 255:123–142
Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M (2009) Brain 132:16–25
Baun M, Pedersen MH, Olesen J (2012) Jansen-Olesen I(32):337–345
Jansen-Olesen I, Hougaard Pedersen S (2018) J Headache Pain 19. https://doi.org/10.1186/s10194-017-0822-2
Tintinalli JE (2010) Emergency Medicine: A Comprehensive Study Guide. McGraw-Hill Companies, New York, pp 1116–1117
Bigal ME, Arruda MA (2010) Headache 50:1130–1143
Bose P, Goadsby PJ (2016) Curr Opin Neurol 29:299–301
Kelman L (2006) Cephalalgia 26:214–220
Halker RB, Vargas BB (2012). Fut Med. https://doi.org/10.2217/EBO.11.391
Durham PL (2006) Headache 46(Suppl 1):S3–S8
Arulmani U, MaassenVanDenBrink A, Villalón CM, Saxena PR (2004) Eur J Pharmacol 500:315–330
Rosenfeld M, Mermod JJ, Amara S, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM (1983) Nature 304:129–135
Conner AC, Hay DL, Howitt SG, Kilk K, Langel U, Wheatley M, Smith DM, Poyner DR (2002) Biochem Soc Trans 30:451–455
Russell FA, King R, Smillie SJ, Kodji X, Brain SD (2014) Reviews 94:1099–1142
Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Nature 298:240–244
Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985) Nature 313:54–56
McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Proc Natl Acad Sci USA 83:5731–5735
Norman A, Henry H, Litwack G (2014) Hormones, Amsterdam, Elsevier, ISBN 978-0-12-369444-7
Kee Z, Kodji X, Brain SD (2018) Front Physiol 9. https://doi.org/10.3389/fphys.2018.01249
https://www.kidsdoc.at/leistenbruch_inguinalhernien.html (retrieved 5 September 2021)
Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM (2002) Pharmacol Rev 54:233–246
Hay DL, Walker CS (2017) Headache 57:625–636
Moretti E (1862) Gior Med Mil Torino 10:392–394
Woakes E (1868) Br Med J II:360–361
Koehler PJ, Isler H (2002) Cephalalgia 22:686–691
Borsook D, May A, Goadsby PJ, Hargreaves R (2012) The migraine brain: imaging, structure, and function, New York: Oxford University Press. pp. 3–16 (https://books.google.de/books?id=5GVVJS_fCAkC&pg=PA3&redir_esc=y#v=onepage&q&f=false)
Du Bois-Reymond E (1860) Archiv für Anatomie und Physiologie, 461–8.
Möllendorff FW (1867) Archiv für pathologische Anatomie und Physiologie und für klinische Medizin 41:385–395
Ravin JG (2017) Hermann von Helmholtz: The Power of Ophthalmoscopy. In: Marmor M, Albert D (eds) Foundations of Ophthalmology, Springer, Cham. 85–93. https://doi.org/10.1007/978-3-319-59641-9_8pp
Woakes E (1869) Schmidt’s Jahrbücher 142:169
Eulenburg A (1871) Lehrbuch der Functionellen Nervenkrankheiten. August Hirschwald, Berlin, p 130
Eulenburg A (1878) Lehrbuch der Nervenkrankheiten. Zweite Völlig Umgearbeitete und, Erweiterte. August Hirschwald, Berlin
Eulenburg A (1887) Zur Aetiologie und Therapie der Migräne, Wiener Med. Presse, 28:3–8 and 54–58
Stoll A (1918) Swiss Patent 79879
https://de.wikipedia.org/wiki/Novartis (retrieved 20 October 2021)
Giger RKA, Engel G (2006) Chimia 60:83–87
Stoll A (1935) Science 82:415–417
Dudley HW, Moir C (1935) BMJ 1:520–523
Stoll A, Hofmann A (1937) US2090430
http://wikimonde.com/article/Denis_Dodart (retrieved 13 October 2021)
Caporael LR (1976) Science 192:21–26
de Candolle AP (1815) Mém Mus Hist Nat 2:401–420
Smakosz A, Kurzyna W, Rudko M, Dasal M (2021). Toxins. https://doi.org/10.3390/toxins13070492
https://en.wikipedia.org/wiki/Annales_Xantenses (retrieved 12 October 2021)
Schiff PL (2006). Am J Pharma Edu. https://doi.org/10.5688/aj700598
Bennett JW, Bentley R (1999) Perspect Biol Med 42:333–355
De Costa C (2002) Lancet 359:1768–1770
van Dongen PW, de Groot AN (1995) Eur J Obscet Gyneco Reprod Biol 60:109–116
https://www.kugener.com/de/pharmazie/69-artikel/3240-ergotine-bonjean.html (retrieved 14 October 2021)
Smith S, Timmis GM (1932) J Chem Soc 1543–1544
Jacobs WA, Craig LC (1935) Science 81:256–257
Jacobs WA, Craig LC (1936) J Org Chem 1:245–253
Stoll A, Hofmann A, Petrzilka T (1951) Helv Chim Acta 34:1544–1576
Hofmann A, Frey AJ, Ott H (1961) Experientia 17:206–207
Jacobs WA, Craig LC (1936) Science 83:38–39
Craig LC, Shedlovsky T, Gould RG, Jacobs WA (1938) J Biol Chem 125:289–298
Stoll A, Hofmann A, Troxler F (1949) Helv Chim Acta 32:506–521
Stoll A, Petrzilka T, Rutschmann L, Hofmann A, Günthard HH (1954) Helv Chim Acta 37:2039–2057
Stadler PA, Hofmann A (1962) Helv Chim Acta 45(1962):2005–2011
Kornfeld EC, Fornefeld EJ, Kline GB, Mann MJ, Jones RG, Woodward RB (1954) J Am Chem Soc 76:5256–5257
Kornfeld EC, Fornefeld EJ, Kline GB, Mann MJ, Morrison DE, Jones RG, Woodward RB (1956) J Am Chem Soc 78:3087–3114
Julia M, Le Goffic F, Igolen J, Baillarge M (1969) Tetrahedron Lett 10:1569–1571
https://medium.com/@zamnesia/the-top-10-naturally-occurring-psychedelics-fa2958ba9146 (retrieved 1 November 2021)
https://en.wikipedia.org/wiki/List_of_substances_used_in_rituals (retrieved 7 November 2021)
Hofmann A, Tscherter H (1960) Experientia 16:414–414
Paulke A, Kremer C, Wunder C, Wurglics M (2015) Schubert-Zsilavecz, Toennes SW. Forensic Sci Int 249:281–293
Nowak J, Wozniakiewicz M, Klepacki P, Sowa A, Koscielniak P (2016) Anal Bioanal Chem 408:3093–3102
https://en.wikipedia.org/wiki/Argyreia_nervosa (retrieved 21 October 2021)
Pochettino M, Cortella AR, Ruiz M (1999) Econ Bot 53:127–132
Capriles JM, Moore C, Albarracin-Jordan J, Miller MJ (2019) Proc Natl Acad Sci USA 116:11207–11212
Moretti C, Gaillard Y, Grenand P, Bévalot F, Prévosto JM (2006) J Ethnopharmacol 106:198–202
Chamakura RP (1994) Forensic Sci Rev 6:2–18
Weil AT, Davis W (1994) J Ethnopharmacol 41:1–8
Davis W, Weil A (1992) Anc Mesoam 3:51–59
Stemmerich K, Schulz K, Peschel A (2021) Böttcher, Arndt T. Toxichem Krimtech 88:51–62
Handovsky H (1920) Archiv für experimentelle Pathologie und Pharmakologie 86:138–158
Wieland H, Konz W, Mittasch H (1934) Justus Liebigs Ann Chem 513:1–25
Hoshino T, Shimodaira K (1935) Justus Liebig’s Ann Chem 520:19–30
Hoshino T, Shimodaira K (1936) Bull Chem Soc Jpn 11:221–224
Stoll A, Troxler F (1955) Peyer, Hofmann A. Helv Chem Acta 38:1452–1472
Akers BP, Ruiz JF, Piper A, Ruck CAP (2011) Econ Bot 65:121–128
Guzmán G (2008) Econ Bot 62:404–412
Wasson RG (1957) Seeking the magic mushroom, Life, May 13, 100–120
Heim R (1957) Revue de Mycologie 22:58–79
Hofmann A, Frey A, Ott H, Petrzilka T, Troxler F (1958) Cell Mol Life Sci 14:397–439
Hofmann A, Heim R, Brack A, Kobel H (1958) Experientia 14:107–109
Passie T, Seifert J, Schneider U, Emrich HM (2002) Addict Biol 7:357–364
https://en.wikipedia.org/wiki/Psilocybin (retrieved 7 November 2021)
Millman L (2019) Fungipedia: A Brief Compendium of Mushroom Lore. Princeton University Press, Princeton, Oxford, p 159
Habermehl G, Hammann PE, Krebs HC, Ternes W (2008) Naturstoffchemie, 3rd edn. Springer, Berlin Heidelberg, pp 203–205
Vollenweider FX, Preller KH (2020) Nat Rev Neurosci 21:611–624
Daws R, Timmermann C, Giribaldi B, Sexton J, Wall MB, Erritzoe D, Roseman L, Nutt D, Carhart-Harris R (2022) Nature Medicine. https://doi.org/10.1038/s41591-022-01744-z
Albert Hofmann (2006) LSD – mein Sorgenkind. Die Entdeckung einer „Wunderdroge“, DTV, München
https://en.wikipedia.org/wiki/History_of_lysergic_acid_diethylamide# (retrieved 22 October 2021)
https://www.ema.europa.eu/en/news/new-restrictions-use-medicines-containing-ergot-derivatives (retrieved 23 October 2021)
Silberstein SD, Crory DC (2003) Headache 43:144–166
Cavero I, Guillon JM (2014) J Pharmacol Toxicol Methods 69:150–161
Hofmann A, Troxler F (1960) CH 344731
Hofmann A, Troxler F (1965) US 3218324
Hofmann A (1978) Pharmacology 16:1–11
Koehler PJ, Tfelt-Hansen PC (2008) Cephalalgia 28:1126–1135
Graham JR, Wolff HG (1938) Arch Neurol Psychiatry 39:737–763
Humphrey PP, Feniuk W, Perren MJ, Beresford IJ, Skingle M, Whalley ET (1990) Ann NY Acad Sci 600:587–598
Twarog BM (1988) Comp Biochem Physiol 91:21–24
Doepfner W, Cerletti A (1958) Int Arch Allergy 12:89–97
Fanchamps A, Doepfner W, Weidman H, Cerletti A (1960) Schweiz Med Wochenschr 90:1040–1046
Sicuteri F (1959) Int Arch Allerg 15:300–307
Utz DZ, Rooke ED, Spittell JA Jr, Bartholomew LG (1965) JAMA 191:983–985
Graham JR (1967) Am J Med Sci 254:1–12
https://www.drugpatentwatch.com/p/NDA/012516 (retrieved 21 November 2021)
https://web.archive.org/web/20210414062750/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Methysergide&doQuery=Submit+Query (retrieved 21 November 2021)
https://pubchem.ncbi.nlm.nih.gov/compound/9681 (retrieved 21 November 2021)
Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A (2013) Expert Opin Pharmacother 14:1599–1610
Saxena PR, Lawang A (1985) Arch Int Pharmacodyn Ther 277:235–252
Colpaert FC, Niemegeers CJ, Janssen PA (1979) Eur J Pharmacol 58:505–509
Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M (2004) Arch Pharmacol 370:114–123
Lambru G, Matharu M (2011) Curr Pain Headache Rep 15:108–117
Majrashi M, Ramesh S, Deruiter J, Mulabagal V, Pondugula S, Clark R, Dhanasekaran M (2017) Multipotent and Poly-therapeutic Fungal Alkaloids of Claviceps purpurea, in Medicinal Plants and Fungi: Recent Advances in Research and Development. Medicinal and Aromatic Plants of the World, Springer Nature Switzerland, 229–252
Leff P (1998) Receptor-Based Drug Design. Marcel Dekker Inc, New York, pp 181–182
Bredberg U, Eyjolfsdottir GS, Paalzow L, Tfelt-Hansen P, Tfelt-Hansen V (1986) Eur J Clin Pharmacol 30:75–77
Halberstadt AL, Nichols DE (2020) Handbook of Behavioral Neuroscience 31:843–863
Cavero I, Guillon JM (2014) J Pharmacol Toxicol Methods 69:150–161
Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL (2000) Circulation 102:2836–2841
Ludwig C, Schmidt A (1868) Arbeiten aus der Physiologischen Anstalt zu Leipzig 1–61
Negri L (2006) Med Secoli 18:97–113
Rapport MM, Green AA, Page IH (1948) J Biol Chem 176:1243–1251
Sjoerdsma A, Palfreyman MG (1990) Ann NY Acad Sci 600:1–8
Rapport MM (1949) J Biol Chem 180:961–969
Hamlin KE, Fischer FE (1951) J Am Chem Soc 73:5007–5008
Twarog BM, Page IH (1953) Am J Physiol 175:157–161
Gaddum JH, Picarelli ZP (1957) Br J Pharmacol Chemother 12:323–328
Gaddum JH (1957) Ann N Y Acad Sci 66:643–648
Peroutka SJ (1994) Neurochem Int 25:533–536
Malenka RC, Nestler EJ, Hyman SE (2009) Sydor A, Brown RY (eds.) Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed), McGraw-Hill Medical. New York, 4
http://www.acnp.org/g4/GN401000039/Ch039.html (retrieved 27 November 2021)
Wesolowska A (2002) Pol J Pharmacol 54:327–341
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=5 (retrieved 19 December 2021)
Vila-Pueyo M (2018) Neurotherapeutics 15:291–303
Weinshank RL, Zgombick JM, Macchi MJ, Branchek TA, Hartig PR (1992) Proc Natl Acad Sci USA 89:3630–3634
Hartig PR, Hoyer D, Humphrey PPA, Martin GR (1996) Trends Pharmacol Sci 17:103–105
Göthert M, Bönisch H, Malinowska B, Schlicker E (2020) Pharmacol Rep 72:271–284
Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC (2013) Science 340:615–619
Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou XE, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE (2013) Science 340:610–614
Yin W, Zhou XE, Yang D, de Waal PW, Wang M, Dai A, Cai X, Huang CY, Liu P, Wang X, Yin Y, Liu B, Zhou Y, Wang J, Liu H, Caffrey M, Melcher K, Xu Y, Wang MW, Xu HE, Jiang Y (2018). Cell Discov. https://doi.org/10.1038/s41421-018-0009-2
Rodríguez D, Brea J, Loza MI, Carlsson J (2014) Structure 22:1140–1151
Peroutka SJ, Howell TA (1994) Neuropharmacology 33:319–324
http://www.wormbook.org/chapters/www_monoamines/monoamines.html (retrieved 28 November 2021)
Huser A, Rohwedder A, Apostolopoulou AA, Widmann A, Pfitzenmaier JE, Maiolo EM, Selcho D, von Essen A, Gupta T, Sprecher SG, Birman S, Riemensperger T, Stocker RF, Thum AS (2012) PLoS ONE 7:e47518. https://doi.org/10.1371/journal.pone.0047518
Bacqué-Cazenave J, Bharatiya R, Barrière G, Delbecque JP, Bouguiyoud N, Di Giovanni G, Cattaert D, De Deurwaerdère P (2020) Int J Mol Sci 21:1649. https://doi.org/10.3390/ijms21051649
McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M (1983) Science 221:762–764
Kang K, Kang S, Lee K, Park M, Back K (2008) Plant Signal Behav 3:389–390
Muszyńska B, Sułkowska-Ziaja K, Ekiert H (2009) Pharmazie 64:479–480
Feldman JM, Lee EM (1985) Am J Clin Nutr 42:639–643
Herraiz T (2000) J Agric Food Chem 48:4900–4904
Bhowal B, Bhattacharjee A, Goswami K, Sanan-Mishra N, Singla-Pareek SL, Kaur C, SoporyS (2021) Int J Mol Sci 22. https://doi.org/10.3390/ijms222011034
Millan MJ, Marin P, Bockaert J, la Cour CM (2008) Trends Pharmacol Sci 29:454–464
https://qmro.qmul.ac.uk/xmlui/handle/123456789/12988 (retrieved 4 December 2021)
Sicuteri F (1972) Headache 1972. 12:69–72
Sicuteri F, Testi A, Anselmi B (1961) Int Arch Allergy Appl Immunol 19:55–58
https://www.niaonline.org/know-your-nia-member-dr-pramod-saxena-loyal-member-of-nia-from-last-50-years/ (retrieved 4 December 2021)
Saxena PR (1974) Eur J Pharmacol 27:99–105
Doenicke A, Siegel E (1987) Schmerz 1:29–34
Saxena PR, Ferrari MD (1989) Trends Pharm Sci 10:200–204
Saxena PR, Ferrari MD (1992) Cephalalgia 12:187–196
Humphrey PPA (2007) Headache 47 [Suppl 1]:S10-S19
Ferrari MD, Goadsby PJ, Roon KI, Lipton RB (2002) Cephalalgia 22:633–658
Saxena PR, Tfelt-Hansen PC (2001) J Headache Pain 2:3–11
Tfelt-Hansen P, De Vries P, Saxena PR (2000) Drugs 60:1259–1287
Bremner DH, Ringan NS, Wishart G (1997) Eur J Med Chem 32:59–69
Bojarski AJ (2006) Curr Top Med Chem 6:2005–2026
Höltje HD, Terzioglu Klip N (2005) Collect Czech Chem Commun 70:1482–1492
Barnes NM, Sharp T (1999) Neuropharmacology 38:1083–1152
Goadsby PJ (1998) Clin Neurosci 5:18–23
Tepper SJ, Rapoport AM, Sheftell FD (2002) Arch Neurol 59:1084–1088
Ahn AH, Basbaum AI (2005). Pain. https://doi.org/10.1016/j.pain.2005.03.008
Sauvage N, Macdonald A, Mallet D (2020) Nature 586:S2–S3
Tfelt-Hansen PC, Pihl T, Hougaard A, Mitsikostas DD (2014) Expert Opin Investig Drugs 23:375–385
Tfelt-Hansen PC, Olesen J (2012) J Headache Pain 13:271–275
Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC (2002) Neurology 59:1011–1014
Do TP, Guo S, Ashina M (2019) J Headache Pain 20. https://doi.org/10.1186/s10194-019-0974-3
Negro A (2021) Martelletti. Expert Opin Pharmacother 22:907–922
Adham N, Kao HT, Schecter LE, Bard J, Olsen M, Urquhart D, Durkin M, Hartig PR, Weinshank RL, Branchek TA (1993) Proc Natl Acad Sci USA 90:408–412
Cohen MP, Kohlman DT, Liang SX, Mancuso V, Victor F, Xu YC, Ying RP, Zacherl DAP, Zhang D (2003) WO 03/084949 (Eli Lilly and Company)
https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019 (retrieved 23 December 2021)
Clemow DB, Johnson KW, Hochstetler HM, Ossipov MH, Hake AM, Blumenfeld AM (2020). J Headache Pain. https://doi.org/10.1186/s10194-020-01132-3
Rissardo JP, Fornari Caprara AL (2020) J Curr Res Sci Med 6:11–14
https://lundbeckfonden.com/sites/lundbeckfonden.com/files/media/document/Short%20Biographies%20of%20the%20Winners%202021.pdf (retrieved 25 December 2021)
Waeber C, Moskowitz MA (2005) Neurology 64:S9–S15. https://doi.org/10.1212/wnl.64.10_suppl_2.s9
Buzzi MG, Moskowitz MA (1990) Br J Pharmacol 99:202–206
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) Cephalalgia 22:54–61
Goadsby PJ, Edvinsson L, Ekman R (1990) Ann Neurol 28:183–187
Goadsby PJ, Edvinsson L (1993) Ann Neurol 33:48–56
Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM (2004) N Engl J Med 350:1104–1110
https://newdrugapprovals.org/2017/01/25/telcagepant-revisited/ (retrieved 25 December 2021)
https://adisinsight.springer.com/drugs/800024645 (retrieved 25 December 2021)
Negro A, Martelletti P (2019) Expert Opin Investig Drugs 28:555–567
Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ (2022) J Clin Med 11. https://doi.org/10.3390/jcm11061656
Holland PR, Goadsby PJ (2018) Neurotherapeutics 15:304–312
https://news.abbvie.com/news/press-releases/fda-approves-qulipta-atogepant-first-and-only-oral-cgrp-receptor-antagonist-specifically-developed-for-preventive-treatment-migraine.htm (retrieved 26 December 2021)
https://www.biohavenpharma.com/investors/news-events/press-releases/12-17-2019 (retrieved 26 December 2021)
https://adisinsight.springer.com/drugs/800011055 (retrieved 25 December 2021)
https://www.biohavenpharma.com/science-pipeline/our-pipeline (retrieved 25 December 2021)
https://de.wikipedia.org/wiki/Inhibitoren_im_Calcitonin-Gene-Related-Peptide-Signalweg (retrieved 27 December 2021)
Cotrell GS (2019) Handb Exp Pharmacol 255:37–64
https://americanmigrainefoundation.org/resource-library/anti-cgrp-treatment-options/ (retrieved 28 December 2021)
https://www.ajmc.com/view/fda-approves-erenumab-first-cgrp-inhibitor-for-prevention-of-migraine (retrieved 28 December 2021)
Lattanzi S, Brigo F, Trinka E, Vernieri F, Corradetti T, Dobran M, Silvestrini M (2019) Drugs 79:417–431
https://americanmigrainefoundation.org/resource-library/fda-approves-fremanezumab/ (retrieved 28 December 2021)
Bigal ME, Rapoport AM, Silberstein SD, Walter S, Hargreaves RJ, Aycardi E (2018) CNS Drugs 32:1025–1037
https://investor.lilly.com/news-releases/news-release-details/lillys-emgalitytm-galcanezumab-gnlm-receives-us-fda-approval (retrieved 28 December 2021)
Lamb YN (2018) Drugs 78:1769–1775
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf (retrieved 28 December 2021)
Diener HC. (2020) InFo Neurologie 22. https://doi.org/10.1007/s15005-020-1370-x
Bekkam M, Mo H, Nichols DE (2012) Org Lett 14:296–298
Lee K, Poudel YB, Glinkerman CM, Boger DL (2015) Tetrahedron 71:5897–5905
Liu H, Jia Y (2017) Nat Prod Rep 34:411–432
Jastrzebski MK, Kaczor AA, Wróbel TM (2022) Molecules 27:7322. https://doi.org/10.3390/molecules27217322
Zhao Y (2010) PhD Thesis, Reduction of Tertiary Benzamides to Benzaldehydes by an in Situ–Generated Schwartz Reagent (Cp2Zr(H)Cl); Formal Synthesis of Lysergic Acid; Queen’s University Kingston: Kingston, ON, Canada
Zhao Y, Snieckus VA (2014) Org Lett 16:390–393
Points GL III, Stout KT, Beaudry CM (2020) Chem Eur J 26:16655–16658
Rathnayake U, Garner P (2021) Org Lett 23:6756–6759
Saá C, Crotts DD, Hsu G, Vollhardt KPC (1994) Synlett 487
Armstrong VW, Coulton S, Ramage R (1976) Tetrahedron Lett 17:4311–4314
Oppolzer W, Francotte E, Bättig K (1981) Helv Chim Acta 64:478–481
Kiguchi T, Hashimoto C, Naito T, Ninomiya I (1982) Heterocycles 19:2279–2282
Rebek J Jr, Tai DF (1983) Tetrahedron Lett 24:859–860
Kurihara T, Terada T, Yoneda R (1986) Chem Pharm Bull 34:442–443
Cacchi S, Ciattini PG, Morera E, Ortar G (1988) Tetrahedron Lett 29:3117–3120
J. B. Hendrickson JB, Wang J (2004) Org Lett 6:3–5.
Moldvai I, Temesvári-Major E, Incze M, Szentirmay É, Gács-Baitz E, Szántay C (2004) J Org Chem 69:5993–6000
Inuki S, Oishi S, Fujii N, Ohno H (2008) Org Lett 10:5239–5242
Kurokawa T, Isomura M, Tokuyama H, Fukuyama T (2009) Synlett 775–778
Fukuyama T, Inoue T, Yokoshima S (2009) Heterocycles 79:373–378
Inuki S, Iwata A, Oishi S, Fujii N, Ohno H (2011) J Org Chem 76:2072–2083
Iwata A, Inuki S, Oishi S, Fujii N, Ohno H (2011) J Org Chem 76:5506–5512
Liu Q, Jia Y (2011) Org Lett 13:4810–4813
Umezaki S, Yokoshima S, Fukuyama T (2013) Org Lett 15:4230–4233
Liu Q, Zhang Y, Xu P, Jia Y (2013) J Org Chem 78:10885–10893
Kanno R, Yokoshima S, Kanai M, Fukuyama T (2018) J Antibiot 71:240–247
Knight B, Harbit R, Smith J (2022). ChemRxiv. https://doi.org/10.26434/chemrxiv-2022-wgq5v
https://www.brandeis.edu/provost/letters/2018-2019/2019-04-02-james-hendrickson.html (retrieved 27 March 2022)
Glorius F (2005) Org Biomol Chem 3:4171–4175
Kim AN, Stoltz BM (2020) ACS Catal 10:13834–13851
Littke AF, Fu GC (2001) J Am Chem Soc 123:6989–7000
Hofmann A, Ott H, Griot R, Stadler PA, Frey AJ (1963) Helv Chim Acta 46:2306–2328
Arcamone F, Bonino C, Chain EB, Ferretti A, Pennella P, Tonolo A, Vero L (1960) Nature 187:238–239
Stoll A, Brack A, Hofmann A, Kobel H (1957) US 2809920 (Sandoz, Basel)
Kybal J, Protiva J, Strnadová, Starý (1961) DE 1201949 (Spofa, Prag)
Amici AM, Spalla C, Scotti T, Minghetti A (1964) DE 1210128. Società Farmaceutici Italia, Milan
Amici AM, Minghetti A, Scotti T, Spalla C, Tognoli L (1967) Appl Microbiol 15:597–602
Amici AM, Minghetti A, Scotti T, Spalla C, Tognoli L (1969) Appl Microbiol 18:464–468
Trejo Hernandez MR, Raimbault M, Roussos S, Lonsane BK (1992) Lett Appl Microbiol 15:156–159
https://royalsocietypublishing.org/doi/pdf/. https://doi.org/10.1098/rsbm.1984.0017 (retrieved 10 April 2022)
Floss HG, Leistner E (2010) Planta Med 76:1389–1389
Floss HG (1976) Tetrahedron 32:873–912
Gröger D (1998) Floss HG (Cordell GA, ed). Alkaloids 50:171–218
Müller R, Wright GD (2019) J Ind Microbiol Biotechnol 46:251–255
Metzger U, Schall C, Zocher G, Unsöld I, Stec E, Li SM, Heide L, Stehle T (2009) Proc Natl Acad Sci USA 106:14309–14314
Rigbers O, Li SM (2008) J Biol Chem 283:26859–26868
Lorenz N, Olšovská J, Šulc M, Tudzynski P (2010) Appl Environ Microbiol 76:1822–1830
Goetz KE, Coyle CM, Cheng JZ, O’Connor SE, Panaccione DG (2011) Curr Genet 57:201–211
Cheng JZ, Coyle CM, Panaccione DG, O’Connor SE (2010) J Am Chem Soc 132:12835–12837
Matuschek M, Wallwey C, Xie X, Li SM (2011) Org Biomol Chem 9:4328–4335
Schardl CL, Panaccione DG, Tudzynski P (2006) The Alkaloids, Elsevier Inc. https://doi.org/10.1016/S1099-4831(06)63002-2
Gerhards N, Neubauer L, Tudzynski P, Li SM (2014) Toxins 6:32813295
Chen JJ, Han MY, Gong T, Yang JL, Zhu P (2017) RSC Adv 7:27384–27396
Wong G, Lim LR, Tan YQ, Go MK, Bell DJ, Freemont PS, Yew WS (2022) Nat Commun 13. https://doi.org/10.1038/s41467-022-28386-6
Riederer B, Han M, Keller U (1996) J Biol Chem 271:27524–27530
Li JJ, Johnson DS, Sliskovic DR, Roth BD (2004) Contemporary Drug Synthesis. John Wiley & Sons Inc, Hoboken, NJ, Chapter 12:161–187
Dowle MD, Coates IH (1984) GB 2124210 (Glaxo)
Humphrey PPA, Feniuk W, Perren MJ, Oxford AW, Brittain RT (1989) Drugs Fut 14:35–39
Burkhardt G, Klein MP (1965) Calvin M 87:591–596
Langheld K (1910) Ber Dtsch Chem Ges 43:1857–1860
Langheld K (1911) Ber Dtsch Chem Ges 44:2076–2087
Dowle MD, Coates IH (1989) US 4816470 (Glaxo)
Oxford AW (1991) US 5037845 (Glaxo)
Fernandez Forner D, Puig Duran C, Prieto Soto J, Vega Noverola A, Moragues Mauri J (1993) EP 605697 (Almirall-Prodesfarma)
Baker R, Matassa VG, Street LJ (1992) EP 497512 (Merck Sharp & Dohme)
Skwierawska A (2003) Pol J Chem 77:329–332
Sanz A, Carril AMG, Matía MP, Novella JL, Alvarez-Builla J (2008) ARKIVOC 53–58
Holman NJ, Friend CL (1999) WO 01/34561 (BASF)
Grandberg II, Zuyanova TI, Afonina NI, Ivanova TA (1967) Dokl Akad Nauk SSSR 176:583–585
Przheval’skii N, Laipanov RK, Tokmakov GP, Nam NL (2016) Russian Chemical Bulletin 65:1709–1715
Pete B, Bitter I, Szántay C Jr, Schön I, Töke L (1998) Heterocycles 48:1139–1149
Pete B, Bitter I, Harsányi K, Töke L (2000) Heterocycles 53:665–673
Robertson AD, Hill AP, Glen RC, Martin GR (1990) GB909012672 (Wellcome)
Robertson AD, Hill AP, Glen RC, Martin GR (1990) EP486666 (Zeneca)
Patel R (1995) GB 9516145 (Zeneca)
Mittapelli V, Ray PC, Chauhan YK, Datta D (2009) Ind J Chem 48B:590–594
Oxford AW, Butina D, Owen MR (1987) EP 303507 (Glaxo)
Blatcher P, Carter M, Hornby R, Owen MR (1994) WO 95/09166 (1995)
Bosch J, Roca T, Armengol M, Fernández-Forner D (2001) Tetrahedron 57:1041–1048
Li X, Qiu R, Wan W, Cheng X, He Y, Hai L, Wu Y (2015) Chem Res Chin Univ 31:539–542
King FD, Gaster LM, Kaumann AJ, Young RC (1995) US 5464864 (SmithKline Beecham)
Borrett GT, Kitteringham J, Porter RA, Shipton MR, Vimal M, Young RC (1999) US 5962501 (SmithKline Beecham)
Reguri BR, Upparapalli S, Kunchithapatham T, Sambashfvam T, Munusamy S (2012) WO2012/147020 (Orchid Chemicals and Pharmaceuticals Ltd)
Macor JE, Wythes MJ (1996) US 5545644 (Pfizer)
Ogilvie RJ (2002) WO 02/50063 (Pfizer)
Ashcroft CP (2005) WO 2005/103035 (Pfizer)
Ashcroft CP, Hellier P, Pettman A, Watkinson S (2011) Org Process Res Dev 15:98–103
Browne DL, Baxendale IR, Ley SV (2011) Tetrahedron 67:10296–10303
Kumar I, Kumar R, Sharma U (2018) Synthesis 50:2655–2677
Dhuguru J, Skouta R (2020). Molecules. https://doi.org/10.3390/molecules25071615
Baumann M, Baxendale IR, Ley SV, Nikbin N (2011) Beilstein J Org Chem 7:442–495
Baeyer A (1866) Liebigs Ann Chem 140:295–296
Baeyer A, Emmerling A (1869) Ber Dtsch Chem Ges 2:679–682
Humphrey GR, Kuethe JT (2006) Chem Rev 106:2875–2911
Taber DF, Tirunahari PK (2011) Tetrahedron 67:7195–7210
Fischer E, Jourdan F (1883) Ber Dtsch Chem Ges 16:2241–2245
Japp FR, Klingemann F (1887) Ber Dtsch Chem Ges 20:2942–2944
Richard Möhlau R (1881) Ber Dtsch Chem Ges 14:171–175
Bischler A (1892) Ber Dtsch Chem Ges 25:2860–2879
Reissert A (1897) Ber Dtsch Chem Ges 30:1030–1053
Madelung W (1912) Ber Dtsch Chem Ges 45:1128–1134
Nenitzescu CD (1929) Bull Soc Chim Romania 11:37–43
Sundberg RJ, Lin LS, Blackburn DE (1969) J Heterocycl Chem 6:441–441
Batcho AD, Leimgruber W (1970) US 3732245 (Hoffmann LaRoche)
Hemetsberger H, Knittel D, Weidmann H (1970) Monatsh Chem 101:161–165
Gassman PG, Van Bergen TJ, Gruetzmacher G (1973) J Am Chem Soc 95:6508–6509
Hegedus LS, Allen GF, Waterman EL (1976) J Am Chem Soc 98:2674–2676
Mori M, Chiba K, Ban Y (1977) Tetrahedron Lett 1037–1040
Baudin JB, Julia SA (1986) Tetrahedron Lett 27:837–840
Hayakawa K, Yasukouchi T, Kanematsu K (1986) Tetrahedron Lett 27:1837–1840
Moskal J, van Leusen AM (1986) J Org Chem 51:4131–4139
Bartoli G, Palmieri G, Bosco M, Dalpozzo R (1989) Tetrahedron Lett 30:2129–2132
Larock RC, Yum EK (1991) J Am Chem Soc 113(1991):6689–6690
Fukuyama T, Chen X, Peng G (1994) J Am Chem Soc 116:3127–3128
Fürstner A, Hupperts A (1995) J Am Chem Soc 117:4468–4475
Wagaw S, Yang BH, Buchwald SL (1999) J Am Chem Soc 121:10251–10263
Cohen MP, Kohlman DT, Liang SX, Mancuso V, Victor F, Xu YC, Ying BP, Zacherl DP, Zhang D (2003) WO 2003084949 (Eli Lilly)
Carniaux JF, Cummins J (2011) WO 2011 123654 (CoLucid)
Deore D, Bhirud SB, Chand P, Naik S, Badgujar S, Baviskar D (2020) WO 2020/095171 Glenmark Life Sciences Ltd)
Cremonesi G, Invernizzi C, Sada M, Feliciani L, Bertolini G (2021) WO 2021/116979 (Olon)
Yasuda N, Cleator E, Kosjek B, Yin J, Xiang B, Chen F, Kuo SC, Belyk K, Mullens PR, Goodyear A, Edwards JS, Bishop B, Ceglia S, Belardi J, Tan L, Song ZJ, DiMichele L, Reamer R, Cabirol FL, Tang WL, Liu G (2017) Org Process Res Dev 21:1851–1858
Xiang B, Belyk K, Reamer RA, Yasuda N (2014) Angew Chem Int Ed 53:8375–8378
Chen F, Molinaro C, Wuelfing WP, Yasuda N, Yin J, Zhong YL, Lynch J, Andreani T (2013) WO 2013169348 (Merck Sharp Dohme)
Leahy DK, Desai LV, Deshpande RP, Mariadass AV, Rangaswamy S, Rajagopal SK, Madhavan L, Illendula S (2012) Org Process Res Dev 16:44–249
Jones G, Jones RK (1973) J Chem Soc Perkin I:26–32
Leahy DK, Fan Y, Desai LV, Chan C, Zhu J, Luo G, Chen L, Hanson RL, Sugiyama M, Rosner T, Cuniere N, Guo Z, Gao Q (2012) Org Lett 14:4938–4941
Luo G, Chen L, Conway CM, Denton R, Keavy D, Signor L, Kostich W, Lentz KA, Santone KS, Schartman R, Browning M, Tong G, Houston JG, Dubowchik GM, Macor JE (2012) J Med Chem 55:10644–10651
Luo G, Dubowchik GM, Macor JE (2013) US 2013/0053570 (BMS)
Roberts DR, Schartman RR, Wie C (2013) EP 3 254 681 (BMS)
Bell IM, Fraley ME, Gallicchio SN, Ginnetti A, Mitchell HJ, Paone DV, Staas DD, Wang C, Zartman CB, Stevenson HE (2012) WO 2012064910 (MSD)
P. Martelletti P, Cipolla F, Capi M, Curto M; Lionetto M (2020) Drugs Fut. https://doi.org/10.1358/dof.2020.45.5.3123467
Cann RO, Chen CPH, Gao Q, Hanson R, Hsieh DH, Li J, Lin D, Parsons RL, Pendri Y, Nielsen RB, Nugent WA, Parker WL, Quinlan S, Reising NP, Remy B, Sausker J, Wang X (2012) Org Process Res Dev 16:1953–1966
Chaturvedula PV, Mercer SE, Pin SS, Thalody G, Xu C, Conway CM, Keavy D, Signor L, Cantor GH, Mathias N, Moench P, Denton R, Macci R, Schartman R, Whiterock V, Davis C, Macor JE, Dubowchik GM (2013) Bioorg Med Chem Lett 23:3157–3161
Vineyard BD, Knowles WS, Sabacky MJ, Bachman GL, Weinkauff DJ (1977) J Am Chem Soc 99:5946–5952
Yamanaka G, Kanou K, Takamatsu T, Takeshita M, Morichi S, Suzuki S, Ishida Y, Watanabe Y, Go S, Oana S, Kawashima H (2021) J Clin Med 10. https://doi.org/10.3390/jcm10010138
Vogl S, Picker P, Mihaly-Bison J, Fakhrudin N, Atanasov AG, Heiss EH, Wawrosch C, Reznicek G, Dirsch VM, Saukel J, Koppa B (2013) J Ethnopharmacol 149:750–771
Kleeberg-Hartmann J, Vogler B, Messlinger K (2021) The Journal of Headache and Pain 22. https://doi.org/10.1186/s10194-021-01235-5
Thompson DF, Saluja HS (2017) J Clin Pharm Ther 42:394–403
Gyorgy P, Kuhn R, Wagner-Jauregg T (1933) Naturwissenschaften 21:560–561
Kuhn R, Reinemund K (1934) Ber Dtsch Chem Ges 67:1932–1936
Karrer P, Schöpp K, Benz F, Pfaehler K (1935) Helv Chim Acta 18:69–79
Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA (1998) Ann Neurol 44:908–912
Fallah R, Shoroki FF, Ferdosian F (2015) Curr Drug Saf 10:132–135
Long R, Zhu Y, Zhou S (2019). Medicine. https://doi.org/10.1097/MD.0000000000014099
Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W (1958) J Am Chem Soc 80:2587–2587
Reyngoudt H, Paemeleire K, Descamps B, De Deene Y, Achten E (2011) Cephalalgia 31:1243–1253
Younis S, Hougaard A, Vestergaard MB, Larsson HBW, Ashina M (2017) Curr Opin Neurol 30:246–262
Slater SK, Nelson TD, Kabbouche MA, LeCates SL, Horn P, Segers A, Manning P, Powers SW, Hershey AD (2011) Cephalalgia 31:897–905
Sazali S, Badrin S, Norhayati MN, Idris NS (2021) BMJ Open11. https://doi.org/10.1136/bmjopen-2020-039358
Crane FL, Hatefi Y, Lester RL, Widmer C (1957) Biochim Biophys Acta 25:220–221
Wolf DE, Hoffmann CH, Trenner NR, Anson DH, Shunk CH, Linn BO, McPherson JF, Folkers K (1958) J Am Chem Soc 80:4752–4752
Morton RA, Gloor U, Schindler O, Wilson GM, Chopard-dit-Jean LH, Hemming FW, Isler O, Leat WMF, Pennock JF, Ruegg R, Schwieter U, Wiss O (1958) Helv Chim Acta 4:2343–2357
Slavin M, Li H, Khatri M (2021) Headache 61:276–286
Maier JA, Pickering G, Giacomoni E, Cazzangia A, Pellegrino (2020) Nutrients 12. https://doi.org/10.3390/nu12092660
Welch KM, Ramadan NM (1995) J Neurol Sci 134:9–14
Dolati S, Rikhtegar R, Mehdizadeh A, Yousefi M (2020) Biol Trace Elem Res 196:375–383
Teigen L, Boes CJ (2015) Cephalalgia 35:912–922
Kovacevic G, Stevanovic D, Bogicevic D, Nikolic D, Ostojic S, Tadic B, Nikolić B, Bosiocic I, Ivančević N, Jovanovic K, Samardzic J, Jancic J (2017) Magnes Res 30:133–141
Avery J, Etheridge L (2021) Arch Dis Child 106:1027–1030
Domitrz I, Cegielska J (2022) Nutrients 14. https://doi.org/10.3390/nu14051089
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We are indebted to the reviewers and Prof. Philip Parsons, Imperial College London, for valuable comments and for careful proofreading.
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In memoriam: Bernd Janssen (1950–2022), my mentor and dear friend (B.S.).
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Ramachanderan, R., Schramm, S. & Schaefer, B. Migraine drugs. ChemTexts 9, 6 (2023). https://doi.org/10.1007/s40828-023-00178-5
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DOI: https://doi.org/10.1007/s40828-023-00178-5