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Zolmitriptan

HCID 60857
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Basic information

CAS
139264-17-8
Standard SMILES
CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
InChIKey
ULSDMUVEXKOYBU-ZDUSSCGKSA-N
Molecular formula
C16H21N3O2
Average molar mass
287.36 g/mol
Monoisotopic mass
287.16337691

Overview

Zolmitriptan is a member of the class of tryptamines that is N,N-dimethyltryptamine in which the hydrogen at position 5 of the indole ring has been replaced by a [(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl group. A serotonin 5-HT1 B and D receptor agonist, it is used for the treatment of migraine. It has a role as an anti-inflammatory drug, a serotonergic agonist and a vasoconstrictor agent. It is a member of tryptamines and an oxazolidinone. It is functionally related to a N,N-dimethyltryptamine.

Names & identifiers

Preferred name
Zolmitriptan
IUPAC
(4S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one
English name
Zolmitriptan
Molecular formula
C16H21N3O2
Molecular weight
287.36

Names & synonyms

zolmitriptan139264-17-8ZomigZomigoroZomig-ZMT311C90AscoTopzolmitriptanumDTXSID8045933Cvt-4272FS66TH3YWNSC-760383
Show more names
Zomibw311c90ZolmitrptanzolmitripanZOLMITRIPTANEZOLIMITRIPTANZuomi quputan
(4S)-4-({3-[2-(dimethylamino)ethyl]-1H-indol-5-yl}methyl)-1,3-oxazolidin-2-one(4S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one4-((3-(2-(Dimethylamino)ethyl)-1H-indol-5-yl)methyl)-2-oxazolidinone(S)-4-((3-(2-(Dimethylamino)ethyl)-1H-indol-5-yl)methyl)-2-oxazolidinoneDTXCID6025933CHEBI:10124311-C-902-Oxazolidinone, 4-((3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)methyl)-, (S)-

Database identifiers

CAS
139264-17-8
PubChem CID
60857
DTXSID
DTXSID8045933
ChEMBL
CHEMBL1185
ChEBI
CHEBI:10124
UNII
2FS66TH3YW

Properties

Computed structural properties

XLogP
2.2
Topological polar surface area
57.4 Ų
Hydrogen bond donors
2
Hydrogen bond acceptors
3
Rotatable bonds
5
Heavy atoms
21
Formal charge
0
Complexity
375

Experimental & physicochemical properties

DrugsPharmaceuticals -> Listed in ZINC15
LogP · 2 items

1.6

0.79

Solubility1.90e-01 g/L
Human Drugs · 3 items

Breast Feeding; Lactation; Milk, Human; Serotonin Receptor Agonists; Serotonin 5-HT1 Receptor Agonists; Triptans; Vasoconstrictor Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Physical DescriptionSolid
Dissociation Constants9.64
Collision Cross Section · 3 items

159.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

160.6 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

164.88 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Physicochemical properties

Safety & regulation

Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.

GHS classification

GHS Classification · 4 items

Warning

H302 (95.2%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P308+P316, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 21 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard information

Hazard Classes and CategoriesAcute Tox. 4 (95.2%)

Toxicology

Treatment · 1 item

There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. (L1712)

Health EffectsSerious cardiac events, including myocardial infarction migth occur. [Wikipedia]
Adverse Effects · 1 item

Dysgeusia is the most commonly observed adverse effect of zolmitriptan in healthy individuals, with the nasal spray causing a more significant impact. This phenomenon is likely attributed to the method of drug administration through the nasal route. Additional minor adverse events reported with intranasal zolmitriptan usage include nasal passage irritation, dizziness, throat irritation, and fatigue. Furthermore, phase 1 trials of the Real Life Intranasal Zolmitriptan Exposure (REALIZE) study revealed that the encountered adverse effects did not result in participants discontinuing the medication.

Chemistry & industry

Pharmacology

ATC Code · 3 items

N02CC03

N - Nervous system

QN - Nervous system

Protein BindingZolmitriptan and its active N-desmethyl metabolite remain approximately 25% bound to plasma proteins over a concentration range of 10-1000 ng/mL.
Pharmacodynamics · 1 item

Zolmitriptan, like other triptans, is a serotonin (5-hydroxytryptamine; 5-HT) receptor agonist, with enhanced specificity for the 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptor subtypes. It is through the downstream effects of 5-HT<sub>1B/1D</sub> activation that triptans are proposed to provide acute relief of migraines. Zolmitriptan is also a vasoconstrictor, leading to possible adverse cardiovascular effects such as myocardial ischemia/infarction, arrhythmias, cerebral and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospastic reactions. In addition, chest/throat/neck/jaw pain, tightness, and/or pressure has been reported, along with the possibility of medication overuse headaches and serotonin syndrome. Patients with phenylketonuria should be advised that ZOMIG-ZMT contains phenylalanine.

Mechanism of Action · 1 item

Migraines are complex physiological events characterized by unilateral throbbing headaches combined with photophobia and other aversions to sensory input. Migraine attacks are generally divided into phases: the premonitory phase, which typically involves irritability, fatigue, yawning, and stiff neck; the headache phase, which lasts for between four and 72 hours; and the postdrome phase, which lasts for up to a day following resolution of pain and whose symptoms are similar to those of the premonitory phase. In addition, neurological deficits, collectively termed migraine aura, may precede the headache phase. The underlying pathophysiology of migraines is a matter of active research but involves both neurological and vascular components. The head pain associated with migraine is thought to be a consequence of activation of the nociceptive nerves comprising the trigeminocervical complex (TCC). Terminals of nociceptive nerves that innervate the dura matter release vasoactive peptides, such as calcitonin gene-related peptide (CGRP), resulting in cranial vasodilation. Finally, when present, migraine aura appears to correlate with a transient wave(s) of cortical depolarization, termed cortical spreading depression (CSD). Triptans, including zolmitriptan, are proposed to act in three ways. The main mechanism is through modulation of nociceptive nerve signalling in the central nervous system through 5-HT<sub>1B/1D</sub> receptors throughout the TCC and associated areas of the brain. In addition, triptans can enhance vasoconstriction, both through direct 5-HT<sub>1B</sub>-mediated dilation of cranial blood vessels, as well as through 5-HT<sub>1D</sub>-mediated suppression of CGRP release. Although triptans are classically described solely in terms of their effects on 5-HT<sub>1B/1D</sub> receptors, they also act as 5-HT<sub>1F</sub> agonists as well. This 5-HT subtype is also found throughout the TCC, but is not present appreciably in cerebral vasculature; the significance of triptan-mediated 5-HT<sub>1F</sub> activation is currently not well described. Additionally, CSD that initiates in the ipsilateral parietal region may exert its effects in a manner that relies on 5-HT<sub>1B/1D</sub> receptor activation, suggesting that triptans may have some effect on CSD-mediated symptoms.

Related reactions

9 records
New reaction record
HRID 128986 reaction equation
HRID 128986As productuspto-grants-1995_11
HRID 128989 reaction equation
HRID 128989As productuspto-grants-1995_11
HRID 229756 reaction equation
HRID 229756As productuspto-grants-2009_07
HRID 343916 reaction equation
HRID 343916As reactantuspto-grants-1999_01
HRID 343917 reaction equation
HRID 343917As productuspto-grants-1999_01
HRID 1392220 reaction equation
HRID 1392220As productuspto-grants-2008_03
HRID 1470540 reaction equation
HRID 1470540As reactantuspto-grants-2015_04
HRID 1608997 reaction equation
HRID 1608997As productuspto-grants-1995_03
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Compound notes

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EC Number
629-919-0
Nikkaji
J694.097H
Melting point
136 · 136-141°C
alpha
22 · D22 -5.79° (c = 0.5 in methanol)
Boiling point
563.3 · 563.3±38.0 °C(Predicted)
Density
1.217 · 1.217±0.06 g/cm3(Predicted)
storage temp.
15 · 15-25°C
solubility
5 mg/ml · Soluble in DMSO at 5mg/ml
pka
9.64 · 9.64(at 25℃)
form
powder
color
white to beige
optical activity
-3 to · [α]/D -3 to -8°, c = 1 in methanol
λmax
225 nm · 225nm(lit.)
Merck
14 · 14,10189
Stability
2 years · Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChI
1S/C16H21N3O2/c1-19(2)6-5-12-9-17-15-4-3-11(8-14(12)15)7-13-10-21-16(20)18-13/h3-4,8-9,13,17H,5-7,10H2,1-2H3,(H,18,20)/t13-/m0/s1
InChIKey
ULSDMUVEXKOYBU-ZDUSSCGKSA-N
SMILES
CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
CAS DataBase Reference
139264 · 139264-17-8(CAS DataBase Reference)
FDA UNII
2 FS66TH3YW · 2FS66TH3YW
NCI Drug Dictionary
zolmitriptan
ATC code
2 CC03 · N02CC03
UNSPSC Code
41116107 · 41116107
NACRES
24 · NA.24
Protein binding
25 % · 25%
Excreted unchanged in urine
60 · 60 (as metabolites)
Volume of distribution
2.4 · 2.4(L/kg)
Biological half-life
2.5 · 2.5-3 / 3-3.5
Symbol(GHS)
7 · GHS07
Signal word
Warning
Hazard statements
302 · H302
Precautionary statements
264 · P264-P270-P301+P312+P330-P501
Hazard Codes
Xi,Xn
Risk Statements
36 · 36/37/38-22
Safety Statements
26 · 26-36
WGK Germany
3 · 3
RTECS
2707000 · RQ2707000
HS Code
29349990 · 29349990
Storage Class
11 · 11 - Combustible Solids
Toxicity
6 mg/kg/43W-I · women,TDLo,oral,6mg/kg/43W-I (6mg/kg),BEHAVIORAL: HEADACHE,Lancet. Vol. 353, Pg. 378, 1999.
Exposure RoutesTopical(nasal); Oral. Mean absolute oral bioavailability is approximately 40%. Food has no affect on the rate and extent of absorption.
Toxicity Summary · 2 items

In pediatric cases, zolmitriptan toxicity did not result in life-threatening complications; however, the common signs of toxicity included tachycardia, dyspnea, and vomiting. Zolmitriptan overdoses have been linked to hypertension, tachycardia, and drowsiness in adults. Furthermore, there have been 2 documented cases of hepatotoxicity associated with zolmitriptan use.

Zolmitriptan binds with high affinity to human 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors leading to cranial blood vessel constriction. Current theories proposed to explain the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of zolmitriptan for the treatment of migraine headache can most likely be attributed to the agonist effects at the 5HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Carcinogen ClassificationNo indication of carcinogenicity to humans (not listed by IARC).
Drug Induced Liver Injury · 6 items

Drug Induced Liver Injury Rank (DILIrank 2.0)

Zolmitriptan

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

Effects During Pregnancy and Lactation◉ Summary of Use during Lactation

Safety data

wgk
3
rtecs
RQ2707000
hs_code
29349990
Toxicity
women,TDLo,oral,6mg/kg/43W-I (6mg/kg),BEHAVIORAL: HEADACHE,Lancet. Vol. 353, Pg. 378, 1999.
risk_code
36/37/38-22
Signal word
Warning
Symbol(GHS)
GHS07
hazard_code
Xi,Xn
safety_code
26-36
Storage Class
11 - Combustible Solids
Hazard statements
H302
Precautionary statements
P264-P270-P301+P312+P330-P501
Biological Half-LifeZolmitriptan has a mean elimination half-life of approximately three hours following oral or nasal administration. Its active N-desmethyl metabolite has a slightly longer (approximately 3.5 hours) half-life.
Metabolism/Metabolites · 3 items

Zolmitriptan is metabolized in the liver, and studies using cytochrome P450 inhibitors like [cimetidine] suggest that it is likely metabolized by CYP1A2, as well as by monoamine oxidase (MAO). Zolmitriptan metabolism results in three major metabolites: an active N-desmethyl metabolite (183C91) as well as inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites.

Zolmitriptan has known human metabolites that include N-Desmethylzolmitriptan and Zolmitriptan N-oxide.

Hepatic. There have been three metabolites identified: indole acetic acid, N -oxide, and N-desmethyl metabolites. However, the N-desmethyl is the only active metabolite. Half Life: The mean elimination half-life of zolmitriptan and of the active N-desmethyl metabolite is 3 hours.

FDA Pharmacological Classification · 6 items

2FS66TH3YW

ZOLMITRIPTAN

Mechanisms of Action [MoA] - Serotonin 1b Receptor Agonists

Mechanisms of Action [MoA] - Serotonin 1d Receptor Agonists

Established Pharmacologic Class [EPC] - Serotonin-1b and Serotonin-1d Receptor Agonist

Zolmitriptan is a Serotonin-1b and Serotonin-1d Receptor Agonist. The mechanism of action of zolmitriptan is as a Serotonin 1b Receptor Agonist and Serotonin 1d Receptor Agonist.

MeSH Pharmacological ClassificationEndogenous compounds and drugs that specifically stimulate SEROTONIN 5-HT1 RECEPTORS. Included under this heading are agonists for one or more of the specific 5-HT1 receptor subtypes.
Absorption, Distribution and Excretion · 4 items

Zolmitriptan tablets have a mean absolute oral bioavailability of approximately 40%, with food having no effect on the rate or extent of absorption. The dosing kinetics are linear over a range of 2.5 to 50 mg with 75% of the eventual Cmax being attained within 1 hour of dosing. The median Tmax for the tablet form is 1.5 hours, while for the orally disintegrating tablet form, it is 3 hours. The AUC across studies was in the range of 84.4-173.8 ng/mL*h while the Cmax was between 16 and 25.2 ng/mL. Zolmitriptan administered as a nasal spray is detected in the plasma within 2-5 minutes, compared to 10-15 minutes for the tablet form; the faster kinetics likely reflect fast absorption across the nasal mucosa. The bioavailability compared to the tablet is 102%, and plasma zolmitriptan concentration is maintained for 4-6 hours after intranasal delivery. The active N-desmethyl metabolite of zolmitriptan has a mean plasma concentration that is roughly two-thirds of zolmitriptan, regardless of dosage route or concentration.

Zolmitriptan is primarily excreted in urine (approximately 65%) and feces (approximately 30%). Within urine, the most common form is the indole acetic acid metabolite (31%), followed by the N-oxide (7%), and N-desmethyl (4%) metabolites; the majority of zolmitriptan recovered in feces remains unchanged.

Zolmitriptan has a volume of distribution between 7 and 8.4 L/kg.

Zolmitriptan has a clearance of 31.5 mL/min/kg for oral tablets and 25.9 mL/min/kg for nasal administration; one-sixth of the clearance is renal.

Cellular LocationsCytoplasm

Uses & manufacturing

Uses · 2 items

Use (kg; approx.) in Germany (2009): ?10

Used in the acute treatment of migraine attacks with or without aura and cluster headaches.

Applications · 4 items

DescriptionZolmitriptan is a selective serotonin receptor agonist of the 1B and 1D subtypes. It is mainly used in the acute treatment of migraine attacks with or without aura and cluster headaches. Zolmitriptan takes effect through binding to human 5-HT1Band 5-HT1Dreceptors, leading to cranial blood vessel constriction and the release of sensory neuropeptides through nerve endings in the trigeminal system.

Usesadrenergic agonist, nasal decongestant

UsesZolmitriptan is a serotonin 5HTID-receptor agonist and used to treat migraine (1,2,3).

General DescriptionZolmitriptan, the second triptan marketed (approved in1997), has a much better bioavailability (40%–48%) thansumatriptan. It is rapidly absorbed after oral or nasal sprayadministration. It also has an orally disintegrating tablet formulation(Zomig ZMT), which can be taken without water.Zolmitriptan undergoes rapid N-demethylation via CYP1A2to a more potent, active metabolite, N-desmethylzolmitriptan,which is 2 to 6 times more potent than the parentdrug. This active metabolite was detected 5 minutesafter dosing and accounts for about two thirds of the plasmaconcentration of the administered dose of the parent drug.284Thus, it is reasonable to assume that the therapeutic effectsand especially the CNS side effects of zolmitriptan must bein part attributed to the plasma levels of this active metabolite,at least until it is further degraded by hepatic MAO-Ato its inactive indole acetic acid derivatives.

Upstream & downstream products

Upstream raw materials

DimethylamineCopper(II) oxideMethanesulfonic acidQuinoline6-Dimethylaminopurine
Additional notes · 1 item

DefinitionChEBI: Zolmitriptan is a member of the class of tryptamines that is N,N-dimethyltryptamine in which the hydrogen at position 5 of the indole ring has been replaced by a [(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl group. A serotonin 5-HT1 B and D receptor agonist, it is used for the treatment of migraine. It has a role as a serotonergic agonist, a vasoconstrictor agent and an anti-inflammatory drug. It is a member of tryptamines and an oxazolidinone. It is functionally related to a N,N-dimethyltryptamine.