Review

Authors: John D McCorvy, Bryan L Roth

Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for disorders ranging from migraine headaches to neuropsychiatric disorders such as schizophrenia and depression. There are 14 distinct serotonin receptors, of which 13 are G protein-coupled receptors (GPCRs), which are targets for approximately 40% of the approved medicines. Recent crystallographic and biochemical evidence has provided a converging understanding of the basic structure and functional mechanics of GPCR activation. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptor, with the antimigraine and valvulopathic drug ergotamine bound. The first serotonin crystal structures not only provide the first evidence of serotonin receptor topography but also provide mechanistic explanations into functional selectivity or biased agonism. This review will detail the findings of these crystal structures from a molecular and mutagenesis perspective for driving rational drug design for novel therapeutics incorporating biased signaling.

Topics: Allosteric Site; Animals; Ergotamine; GTP-Binding Proteins; Heart Valve Diseases; Humans; Migraine Disorders; Models, Molecular; Protein Conformation; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2B; Receptors, Serotonin; Serotonin Receptor Agonists; Signal Transduction; Vasoconstrictor Agents

PubMed: 25601315
DOI: 10.1016/j.pharmthera.2015.01.009

Review

Authors: N H Raskin

Headache-prone patients have many highly effective therapeutic options open to them. Used only at the time of headache, sumatriptan succinate by mouth or injection and dihydroergotamine nasal spray are novel choices now or soon to be available. The original migraine therapy, ergotamine, is highly effective in its rectal suppository formulation, when used at a subnauseating dosage. Valproate sodium is the latest addition to the many therapies available for long-term stabilization.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Ergotamine; Headache; Humans; Migraine Disorders; Sumatriptan

PubMed: 7975570
DOI: No ID Found

Authors: J N Blau

Topics: Alcoholic Beverages; Aniline Compounds; Blood Vessels; Cerebrovascular Circulation; Child; Conjunctiva; Constriction; Diet; Dilatation; Electroencephalography; Ergotamine; Female; Humans; Imidazoles; Methysergide; Migraine Disorders; Pregnancy; Psychotherapy; Research; Serotonin; Sleep; Tyramine

PubMed: 5090766
DOI: 10.1136/bmj.2.5764.751

Review

Authors: Kasja Rabe, Zaza Katsarava

Headache associated with the chronic use of medications has become a significant problem in the management of headache. Typically, patients overusing analgesics suffer from tension headache, whereas those over-using triptans may experience daily migraine-type headaches or an increase in the frequency of migraine attacks. The treatment of choice in such cases is withdrawal of the medication followed as early as possible by medicinal prophylaxis of the primary headache.

Topics: Acute Disease; Analgesics; Analgesics, Non-Narcotic; Chronic Disease; Ergotamine; Female; Headache; Headache Disorders, Secondary; Humans; Male; Migraine Disorders; Prognosis; Recurrence; Serotonin Receptor Agonists; Sumatriptan; Tension-Type Headache; Time Factors; Vasoconstrictor Agents

PubMed: 16995362
DOI: 10.1007/BF03364717

Review

Authors: E R PERKS

Topics: Amphetamine; Amphetamines; Anesthesia; Anesthetics; Antidepressive Agents; Chlorpromazine; Ephedrine; Ergotamine; Hydrazines; Hypnotics and Sedatives; Iproniazid; Isocarboxazid; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nialamide; Pharmacology; Phenelzine; Phentolamine; Prednisolone; Procaine; Serotonin; Toxicology; Tranylcypromine; Vasopressins

PubMed: 14174638
DOI: 10.1111/j.1365-2044.1964.tb00392.x

Authors: W B Matthews

Classical migraine, including incapacitating visual field defects, repeatedly developed in five young men immediately after blows to the head while playing football and in no other circumstances. A similar condition occurred in a professional boxer and an isolated attack in a boy footballer. Prophylactic treatment with ergotamine tartrate may not be wholly successful and it may be necessary to give up the sport. Any unitary theory of causation of attacks of migraine must account for prodromal symptoms immediately after head injury.

Topics: Adult; Athletic Injuries; Boxing; Child; Craniocerebral Trauma; Ergotamine; Humans; Male; Migraine Disorders; Sports Medicine

PubMed: 5022042
DOI: 10.1136/bmj.2.5809.326

Clinical Trial

Authors: D A Orton, R J Richardson

Adverse reactions to ergotamine were noted in 16 out of 41 studies in which therapeutic doses of the drug were given to normal, healthy volunteers. In 17 of the studies 0.25 mg ergotamine was given by injection, 6 i.v. and 11 i.m., in 20 studies 2 mg ergotamine was given by mouth, and 4 subjects received 2 mg ergotamine by suppository. Plasma and urinary ergotamine was measured by radio-immunoassay. Adverse reactions were significantly more frequent in subjects in whom plasma ergotamine exceeded 1.8 ng/ml. Pharmacokinetic data derived from the study are presented and their relevance to the therapeutic use of ergotamine are discussed.

Topics: Administration, Oral; Adolescent; Adult; Ergotamine; Female; Humans; Injections, Intramuscular; Injections, Intravenous; Male; Suppositories

PubMed: 7088766
DOI: 10.1136/pgmj.58.675.6

Review

Authors: J G Edmeads

Recent advances in migraine therapy include the recognition of analgesic or ergotamine abuse as a cause of chronic daily migraine, the introduction of effective non-narcotic drugs such as chlorpromazine, dihydroergotamine and corticosteroids for the treatment of intractable migraine attacks, the increased number of beta-blockers now recognized as effective prophylactic agents and the introduction of calcium-channel blockers for prophylaxis. There is a sufficient variety of antimigraine drugs, and therapy should be successful for most sufferers.

Topics: Acute Disease; Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Analgesics; Calcium Channel Blockers; Chlorpromazine; Dihydroergotamine; Ergotamine; Humans; Methysergide; Migraine Disorders; Narcotics; Pizotyline

PubMed: 2891428
DOI: No ID Found

Authors: Sven-Oliver Herter, Hajo Haase, Matthias Koch...

Ergot alkaloids (EAs) formed by fungi are one of the most common food contaminants worldwide, affecting cereals such as rye, wheat, and barley. To accurately determine the level of contamination and to monitor EAs maximum levels set by the European Union, the six most common EAs (so-called priority EAs) and their corresponding epimers are quantified using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The quantification of EAs in complex food matrices without appropriate internal standards is challenging but currently carried out in the standard method EN 17425:2021 due to their commercial unavailability. To address the need for isotopically labeled EAs, we focus on two semi-synthetic approaches for the synthesis of these reference standards. Therefore, we investigate the feasibility of the -demethylation of native ergotamine to yield norergotamine, which can subsequently be remethylated with an isotopically labeled methylating reagent, such as iodomethane (CD-I), to yield isotopically labeled ergotamine and its -epimer ergotaminine. Testing the isotopically labeled ergotamine/-inine against native ergotamine/-inine with HPLC coupled to high-resolution HR-MS/MS proved the structure of ergotamine-CD and ergotaminine-CD. Thus, for the first time, we can describe their synthesis from unlabeled, native ergotamine. Furthermore, this approach is promising as a universal way to synthesize other isotopically labeled EAs.

Topics: Ergotamine; Carbon Isotopes; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Isotope Labeling

PubMed: 38668624
DOI: 10.3390/toxins16040199

Authors: Hannes Jacob, Pauline Braekow, Rebecca Schwarz...

Ergotamine (2'-methyl-5'α-benzyl-12'-hydroxy-3',6',18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus . Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT-serotonin receptors or H-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H-TG (mouse which exhibits cardiac-specific overexpression of the human H-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT-serotonin receptor). An amount of 10 µM ergotamine increased the left ventricular force of contraction in isolated retrogradely perfused spontaneously beating heart preparations of both 5-HT-TG and H-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergotamine 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, that were attenuated by 10 µM of the H-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT-serotonin receptors as well at human H-histamine receptors. Ergotamine acts as an agonist on H-histamine receptors in the human atrium.

Topics: Animals; Humans; Mice; Ergotamine; Heart Atria; Myocardial Contraction; Receptors, Histamine; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Receptors, Histamine H4

PubMed: 36902177
DOI: 10.3390/ijms24054749