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

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 (pEC(50): 6.3, 6.9 and 6.1, respectively ) and basilar artery (pEC(50) 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-H T 1.0, sumatriptan 0.85; basilar artery: eletriptan 0.77, 5-HT 0.98, sumatr iptan 0.89). Contractions evoked by eletriptan were antagonised by the 5-HT 1B/1D receptor antagonist GR125743 (N-[4-methoxy-3-(4-methyl piperazin-1-yl )phenyl]-3-methyl-4-(4-pyridyl)benzamide) with pA(2) values of 9.1 in saphe nous vein and 9.4 in basilar artery. Affinity estimates (pK(A)) for 5-HT an d sumatriptan determined from receptor alkylation studies in saphenous vein were 6.6 and 6.3, respectively, compared to the apparent equilibrium disso ciation constant (pK(P)) for eletriptan of 6.8. The rank order of relative intrinsic efficacies (epsilon) was 5-HT > sumatriptan > eletriptan. Thus, e letriptan required greater receptor occupancy (4.4-fold) to evoke an equiva lent contraction to 5-HT and sumalriptan in dog isolated saphenous vein. Th ese data demonstrate that eletriptan is a potent partial agonist at the can ine vascular 5-HT1B receptor. (C) 1999 Elsevier Science B.V. All rights res erved.