Characterisation of the contractile activity of eletriptan at the canine vascular 5-HT1B receptor

• Published in: European journal of pharmacology Vol. 367; no. 2-3; pp. 283 - 290
• Main Authors: GUPTA, P, SCATCHARD, J, NAPIER, C, MCHARG, A, WALLIS, R
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 19.02.1999
• Subjects: Alkylation; Animals; Basilar Artery - drug effects; Benzamides - pharmacology; Biological and medical sciences; Cardiovascular system; Dogs; Female; In Vitro Techniques; Indoles - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Pyridines - pharmacology; Pyrrolidines - pharmacology; Receptors, Serotonin - drug effects; Saphenous Vein - drug effects; Serotonin Antagonists - pharmacology; Sumatriptan - pharmacology; Tryptamines; Vasoconstrictor Agents - pharmacology; Vasodilator agents. Cerebral vasodilators; Fissipedia; Carnivora; Agonist; Sumatriptan; Antimigrainous agent; Eletriptan; Smooth muscle; 5-HT1 Serotonine receptor; Muscle contraction; In vitro; Biological activity; Vertebrata; Mammalia; Animal; Blood vessel; Affinity; Circulatory system; Mechanism of action; Dog; Comparative study
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(98)00926-1

The functional activity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]- 1 H-indole) at the contractile serotonin (5-hydroxytryptamine; 5-HT) '1B-like' receptor in dog isolated saphenous vein and basilar artery was investigated. Eletriptan, like 5-HT and sumatriptan potently contracted saphenous vein (pEC50: 6.3, 6.9 and 6.1, respectively) and basilar artery (pEC50 7.2, 7.5 and 6.8, respectively). The maximum responses evoked by eletriptan was, unlike sumatriptan, significantly lower than that to 5-HT (intrinsic activity saphenous vein: eletriptan 0.57, 5-HT 1.0, sumatriptan 0.85; basilar artery: eletriptan 0.77, 5-HT 0.98, sumatriptan 0.89). Contractions evoked by eletriptan were antagonised by the 5-HT1B/1D receptor antagonist GR125743 (N-[4-methoxy-3-(4-methyl piperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide) with pA2 values of 9.1 in saphenous vein and 9.4 in basilar artery. Affinity estimates (pKA) for 5-HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6.6 and 6.3, respectively, compared to the apparent equilibrium dissociation constant (pKp) for eletriptan of 6.8. The rank order of relative intrinsic efficacies (epsilon) was 5-HT > sumatriptan > eletriptan. Thus, eletriptan required greater receptor occupancy (4.4-fold) to evoke an equivalent contraction to 5-HT and sumatriptan in dog isolated saphenous vein. These data demonstrate that eletriptan is a potent partial agonist at the canine vascular 5-HT1B receptor.