Ergotamine
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Ergotamine
Systematic (IUPAC) name
(6aR,9R)-N-((2R,5S,10aS,10bS)- 5-benzyl-10b-hydroxy-2-methyl- 3,6-dioxooctahydro-2H-oxazolo[3,2-a pyrrolo[2,1-cpyrazin-2-yl) -7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg quinoline-9-carboxamide
Identifiers
CAS number	113-15-5
ATC code	N02CA02
PubChem	9787
Chemical data
Formula	C33H35N5O5
Mol. mass	581.66 g/mol
Pharmacokinetic data
Bioavailability	?
Metabolism	hepatic
Half life	?
Excretion	renal
Therapeutic considerations
Pregnancy cat.	X(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	Oral

Ergotamine is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It possesses structural similarity to several neurotransmitters, and has biological activity as a vasoconstrictor. It is used medicinally for treatment of acute migraine attacks (sometimes in combination with caffeine), and to induce childbirth and prevent post-partum haemorrhage. It was first isolated from the ergot fungus by Arthur Stoll at Sandoz in 1918 and marketed as Gynergen in 1921. ^[1]

Mechanism of action

The mechanism of action of ergotamine is complex.^[2] The molecule shares similarity with neurotransmitters such as serotonin, dopamine, and adrenaline and can thus bind to several cell receptors acting both as agonist and antagonist in signal transduction within cellular tissues. The anti-migraine effect is due to constriction of the intercranial extracerebral blood vessels through the 5-HT_1B receptor, and by inhibiting trigeminal neurotransmission by 5-HT_1D receptors. Ergotamine also has effects on the dopamine and noradrenaline receptors. It is its action on the D2 dopamine and 5-HT_1A receptors that can cause some side effects. ^[3]

Biosynthesis

Ergotamine is a secondary metabolite (natural product) and the principal alkaloid produced by the ergot fungus, Claviceps purpurea, and related fungi in the family Clavicipitaceae. Its biosynthesis in these fungi requires the amino acid L-tryptophan and dimethylallyl diphosphate. These precursor compounds are the substrates for the enzyme, dimethylallyl-tryptophan (DMAT) synthase, catalyzing the first step in ergot alkaloid biosynthesis, i.e., the prenylation of L-tryptophan. Further reactions, involving methyltransferase and oxygenase enzymes, yield the ergoline, lysergic acid. Lysergic acid (LA) is the substrate of lysergyl peptide synthetase, a nonribosomal peptide synthetase, which covalently links LA to the amino acids, L-alanine, L-proline, and L-phenylalanine. Enzyme-catalyzed or spontaneous cyclizations, oxygenations/oxidations, and isomerizations at selected residues precede, and give rise to, formation of ergotamine.^[4]

Drug uses

Ergotamine is also a precursor of LSD, lysergic acid diethylamide. It produces vasoconstriction peripherally. It damages the peripheral epithelium and in high doses is conducive to the creation of vascular stasis, thrombosis and gangrene. It can increase uterine contractivity and occasionally is used therapeutically immediately post-partum to decrease uterine bleeding. It continues to be prescribed for migraine. Contraindications include: atherosclerosis, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy, pruritus, Raynaud's syndrome, and renal disease. ^[5]

See also

• Cafergot, an abortive migraine treatment with ergotamine and caffeine.
• http://www.sandoz.com/assets/content/en/Sandoz_Virtual_History/index.shtml

References

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