ERGOTAMINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C33H35N5O5
Molecular Weight	581.6615
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12CCCN1C(=O)[C@H](CC3=CC=CC=C3)N4C(=O)[C@](C)(NC(=O)[C@H]5CN(C)[C@]6([H])CC7=CNC8=C7C(=CC=C8)C6=C5)O[C@@]24O

InChI

InChIKey=XCGSFFUVFURLIX-VFGNJEKYSA-N

InChI=1S/C33H35N5O5/c1-32(35-29(39)21-15-23-22-10-6-11-24-28(22)20(17-34-24)16-25(23)36(2)18-21)31(41)38-26(14-19-8-4-3-5-9-19)30(40)37-13-7-12-27(37)33(38,42)43-32/h3-6,8-11,15,17,21,25-27,34,42H,7,12-14,16,18H2,1-2H3,(H,35,39)/t21-,25-,26+,27+,32-,33+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C33H35N5O5
Molecular Weight	581.6615
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	6 / 6
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17149427

The isolation and naming of ergotamine by Stoll occurred in 1925 but the complete elucidation of structure was not achieved until 1951, with synthesis following some 10 years later. Current sources of ergotamine include the isolation from field ergot and fermentation broth, as well as synthesis via coupling of (+)-lysergic acid with the appropriate synthetic peptidic moiety. Ergotamine was introduced into world commerce in 1921, and is currently marketed as its water soluble tartrate salt. Ergotamine is a partial agonist at various tryptaminergic receptors (including the serotonin receptor [5-HT2]) and at various α-adrenergic receptors in blood vessels and various smooth muscles. It is likely that the major activity of ergotamine and related alkaloids is one of agonism at the 5-HT1B/1D receptors, just as with the “triptan” antimigraine compounds. FDA-labeled indications for ergotamine tartrate are in the abortion or prevention of vascular headaches, such as migraine, migraine variant, cluster headache, and histaminic cephalalgia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serotonin 1a (5-HT1a) receptor 171 Target ID: CHEMBL214 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8397171	Agonist 2662	0.34 nM [Ki]
Serotonin 1b (5-HT1b) receptor 45 Target ID: CHEMBL1898 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8397171	Agonist 2662	5.4 nM [Ki]
Serotonin 1d (5-HT1d) receptor 52 Target ID: CHEMBL1983 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8397171	Agonist 2662	0.4 nM [Ki]
Serotonin 1e (5-HT1e) receptor 6 Target ID: CHEMBL2182 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8397171	Agonist 2662	9.4 nM [Ki]
Serotonin 2b (5-HT2b) receptor 60 Target ID: CHEMBL1833 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11104741	Partial Agonist 288	3.0 nM [Ki]
Adrenergic receptor alpha-1 169 Target ID: CHEMBL2094251 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8073910 \| https://www.ncbi.nlm.nih.gov/pubmed/2881518	Antagonist 2760
Adrenergic receptor alpha-2 113 Target ID: CHEMBL2095158 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2881518	Partial Agonist 288

Conditions

Condition	Modality	Highest Phase	Product
Migraine 103 Sources: https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=237166	Primary	Approved 8360	ERGOMAR Approved Use Ergomar® is indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants or a so-called "histaminic cephalalgia". Launch Date 4.1472E11
Migraine 103 Sources: http://www.medsafe.govt.nz/profs/Datasheet/c/cafergottab.pdf	Primary	Approved 8360	CAFERGOT Approved Use Treatment of acute attacks of migraine with or without aura in adults.
Migraine 103 Sources: http://www.horizonpharma.com/migergot/	Primary	Approved 8360	MIGERGOT Approved Use MIGERGOT is indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants or so-called “histaminic cephalalgia.” Ergotamine tartrate and caffeine suppositories should only be used for migraine headaches as they are not effective for other types of headaches and they lack analgesic properties. Launch Date 4.33987191E11

C_max

Value	Dose	Co-administered	Analyte	Population
21.4 pg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3732370/	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:		ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
454 pg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3732370/	2 mg single, rectal dose: 2 mg route of administration: Rectal experiment type: SINGLE co-administered:		ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
4.38 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3932078/	3.89 μg/kg bw single, intravenous dose: 3.89 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
61 pg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3732370/	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1.36 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3932078/	1.01 μg/kg bw single, intravenous dose: 1.01 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
2.04 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3932078/	1.94 μg/kg bw single, intravenous dose: 1.94 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
1216 pg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3732370/	2 mg single, rectal dose: 2 mg route of administration: Rectal experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
2.15 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3932078/	3.89 μg/kg bw single, intravenous dose: 3.89 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
2.08 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3932078/	1.01 μg/kg bw single, intravenous dose: 1.01 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
2.13 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3932078/	1.94 μg/kg bw single, intravenous dose: 1.94 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
3.35 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3732370/	2 mg single, rectal dose: 2 mg route of administration: Rectal experiment type: SINGLE co-administered:	ERGOTAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
20 mg single, oral Overdose Dose: 20 mg Route: oral Route: single Dose: 20 mg Co-administed with:: caffeine, p.o(2000 mg, single) Sources: https://pubmed.ncbi.nlm.nih.gov/23243949	healthy, 21 n = 1 Health Status: healthy Age Group: 21 Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/23243949	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea Vomiting (severe) Dizziness Blood pressure decreased Peripheral vasoconstriction Paresthesia Cyanosis peripheral Angina Sources: https://pubmed.ncbi.nlm.nih.gov/23243949
2 mg single, oral Recommended Dose: 2 mg Route: oral Route: single Dose: 2 mg Co-administed with:: caffeine, p.o(200 mg, single) Sources: https://pubmed.ncbi.nlm.nih.gov/1653139 Page: p.319	unhealthy, 40+/-10 n = 289 Health Status: unhealthy Condition: Migraine Age Group: 40+/-10 Sex: M+F Population Size: 289 Sources: https://pubmed.ncbi.nlm.nih.gov/1653139 Page: p.319	Disc. AE: Depression, Vertigo... AEs leading to discontinuation/dose reduction: Depression Vertigo Blurred vision Arrhythmia Hypersensitivity Migraine aggravated Urticaria Dyspnoea Fatigue Tachycardia Vagal reaction Dizziness Tinnitus Sources: https://pubmed.ncbi.nlm.nih.gov/1653139 Page: p.319
2 mg single, oral Recommended Dose: 2 mg Route: oral Route: single Dose: 2 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1399547 Page: p.2	unhealthy n = 41 Health Status: unhealthy Condition: Migraine Sex: M+F Population Size: 41 Sources: https://pubmed.ncbi.nlm.nih.gov/1399547 Page: p.2	Disc. AE: Nausea, Lightheadedness... AEs leading to discontinuation/dose reduction: Nausea (2.4%) Lightheadedness (2.4%) Sources: https://pubmed.ncbi.nlm.nih.gov/1399547 Page: p.2

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1709 inhibitor 1579

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1909	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/18043468/	yes [Ki 13 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1709	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC152687/; https://pubmed.ncbi.nlm.nih.gov/24978905/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313968/	yes		yes (co-administration study) Comment: Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, and troleandomycin) has been associated with acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC152687/; https://pubmed.ncbi.nlm.nih.gov/24978905/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313968/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:64318	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:64318
ZINC	ZINC000052955754	http://zinc15.docking.org/substances/ZINC000052955754

PubMed

Title	Date	PubMed
A case of multiple arterial thromboses after oral contraceptives and ergotamine.	1967 Apr	6023455
[Severe generalized arteriospasm after a minimal therapeutic dose of ergotamine].	1972 Dec 14	4347498
[Severe arterial spasms after the use of Ergotamine].	1972 Feb 8	5015803
[Spasms of the main muscular arteries in the extremities following ingestion of ergotamine-containing drugs].	1973 Apr 20	4695411
Arterial spasm associated with oral ergotamine therapy.	1973 Dec	4775957
Ergotism. Unilateral brachial artery thrombosis secondary to ergotamine tartrate.	1973 Jun	4712163
[Acute ischemia of the lower limbs due to ergotamine-induced arteriospasm].	1973 Nov 30	4792079
[Chronic ergotamine poisoning after migraine treatment].	1974	4408875
Ergotamine-induced venous thrombosis.	1974 Apr	4449779
Ischaemic lateral popliteal nerve palsy due to ergot intoxication.	1974 Dec	4375174
[Ergotamine as a cause of arterial insufficiency].	1974 Oct 10	4423231
[Letter: Coronary spasm following ergotamine medication].	1975 Sep 5	809691
Peripheral vascular spasm due to ergotamine tartrate.	1977 Dec	271785
[Alarming course of drug-induced ergotism following prolonged use of ergotamine tartatare].	1977 Feb 18	403449
Myocardial ischaemia in migraine sufferers taking ergotamine.	1978 Jan	625457
[Bilateral vascular papillitis following ergotamin medication (author's transl)].	1978 Nov	732190
Angina pectoris and sudden death in the absence of atherosclerosis following ergotamine therapy for migraine.	1979 Jul	463911
[Non-invasive method for recognition of coronary artery spasm: 201thallium sequential scintigraphy of the myocardium after ergotamine provocation (author's transl)].	1980 Apr 11	7363818
Reversal of ergotamine-induced arteriospasm by mechanical intra-arterial dilatation.	1980 Dec 13	6108450
Acute myocardial infarction induced by ergotamine tartrate: possible role of coronary arterial spasm.	1981 Jun	6786144
[A case report of acute myocardial infarction induced by ergotamine tartrate (author's transl)].	1981 Mar	6789432
Ergotamine abuse: results of ergotamine discontinuation, with special reference to the plasma concentrations.	1982 Dec	7159921
Arterial complications of migraine treatment with methysergide and parenteral ergotamine.	1982 Jul 24	6807440
Myocardial infarction following administration of sublingual ergotamine.	1982 Sep	7105868
[Myocardial infarct during ergotamine medication in a young man with normal coronary arteries].	1983 Apr 22	6839985
[Ergotamine-induced spasm of the extremities with dorsalis pedis gangrene].	1983 Jun 10	6410215
[Ergotism causing peripheral arterial occlusion in the hand].	1983 Mar	6852679
Screening for new compounds with antiherpes activity.	1984 Oct	6517562
Reversible cerebral arteriopathy associated with the administration of ergot derivatives.	1984 Sep	6437683
[Ergotism with cerebral complications. Case report and review of the literature].	1986 Apr 5	3961460
Ergotamine-induced peripheral ischaemia reversed by oral thymoxamine hydrochloride.	1986 Jan	2936675
Amelioration of ergotamine withdrawal symptoms with naproxen.	1987 Mar	3298163
[Myocardial infarct caused by an ergotamine tartrate-troleandomycin combination].	1988 Sep-Oct	3146787
St. Anthony's fire: a medieval disease in modern times: case history.	1989 Oct	2802263
[Generalized brain edema and cerebral infarct in ergotamine abuse: imaging by computerized tomography, magnetic resonance tomography and angiography].	1989 Sep	2591142
Mitral and aortic valve disease associated with ergotamine therapy for migraine. Report of two cases and review of literature.	1990 Jan	2403780
Ergotamine headache mistaken for temporal arteritis.	1990 Sep	2241124
Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain.	1993 Apr 15	7682702
[Daily chronic headache in patients with migraine induced by abuse of ergotamine-analgesics: response due to a protocol of outpatient treatment].	1993 Aug-Sep	8104438
Ergotamine-induced fetal stress: review of side effects of ergot alkaloids during pregnancy.	1993 Sep	8282144
[Ergotamine-induced rectal lesions in asymptomatic patients].	1994	8197748
Variant angina complicating ergot therapy of migraine.	1994 Apr	8162760
Cloning and characterisation of the human 5-HT5A serotonin receptor.	1994 Dec 5	7988681
Ergot induced peripheral vascular insufficiency, non-interventional treatment.	1994 Mar	7912993
Ergotamine-induced headache can be sustained by sumatriptan daily intake.	1994 Oct	7828198
Prinzmetal-variant angina in a patient using zolmitriptan and citalopram.	2010 Feb	20159412
Cytotoxicity and accumulation of ergot alkaloids in human primary cells.	2011 Apr 11	21295106
Structural features for functional selectivity at serotonin receptors.	2013 May 3	23519215
Structural basis for molecular recognition at serotonin receptors.	2013 May 3	23519210
FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1.	2013 Sep 5	23769903

Patents

Sample Use Guides

In Vivo Use Guide

MIGERGOT - ergotamine tartrate and caffeine rectal suppository. One suppository at start of attack; second suppository after 1 hour, if needed for full relief. Two suppositories is the maximum dose for an individual attack. Cafergot (Ergotamine tartrate 1 mg and Caffeine 100 mg Tablets) First attack: The first time Cafergot is taken, an initial dose of 2 Cafergot tablets orally, is recommended. If relief is not obtained within half an hour, a further tablet should be administered; this may be repeated at half-hourly intervals, but the maximum daily dose of 6 tablets should not be exceeded. Subsequent attacks: If the pain persists, take 1 tablet every half an hour up to the maximum daily dose of 6 tablets. The maximum weekly dose is 10 tablets. ERGOMAR SUBLINGUAL- ergotamine tartrate tablet For best results, dosage should start at the first sign of an attack. Early Administration Gives Maximum Effectiveness. At the first sign of an attack or to relieve symptoms after onset of an attack, one 2 mg tablet is placed under the tongue. Another tablet should be taken at half-hour intervals thereafter, if necessary, but dosage must not exceed three tablets in any 24hour period. Total weekly dosage should not exceed five tablets (10 mg) in any one week. Ergomar® Sublingual Tablets should not be used for chronic daily administration.

Route of Administration: Other

In Vitro Use Guide

The bovine anterior pituitary cells were implanted on culture tubes using D-valine minimal essential medium with serum to suppress the overgrowth of fibroblasts and then maintained in L-valine Dulbecco's modified Eagle medium. (3H)-Uridine uptake by these cells was suppressed by ergotamine at a concentration varing from 1-10 uM

Substance Class	Chemical Created by `admin` on `Wed Jul 05 22:31:22 UTC 2023` Edited by `admin` on `Wed Jul 05 22:31:22 UTC 2023`
Record UNII	PR834Q503T
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ERGOTAMINE

Official Name

English

ERGOTAMINE [HSDB]

Common Name

English

Ergotamine [WHO-DD]

Common Name

English

ERGOTAMINE [VANDF]

Common Name

English

ERGOTAMINE [MI]

Common Name

English

ergotamine [INN]

Common Name

English

NSC-95090

Code

English

5′α-benzyl-12′-hydroxy-2′-methyl-3′,6′,18-trioxoergotaman

Systematic Name

English

ERGOTAMAN-3',6',18-TRIONE, 12'-HYDROXY-2'-METHYL-5'-(PHENYLMETHYL)-, (5'.ALPHA.)-

Common Name

English

CODERGOCRINE MESILATE IMPURITY C [EP IMPURITY]

Common Name

English

Classification Tree Code System Code

DEA NO.

8676