Pharmacological characterization of almotriptan: an indolic 5-HT receptor agonist for the treatment of migraine

Almotriptan (3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1 H-indole) has been studied in several models predictive of activity and se lectivity at 5-HT receptors. Almotriptan showed low nanomolar affinity for the 5-HT1B and 5-HT1D receptors in several species, including the human, wh ile affinity for 5-HT receptors other than 5-HT1B/1D was clearly less. Affi nity for 5-HT7 and 5-HT1A receptors was approximately 40 and 60 times lower than that for 5-HT1B/1D receptors, respectively. Almotriptan did not exhib it significant affinity for several non-5-HT receptors studied up to 100 mu M. Almotriptan inhibited forskolin-stimulated cyclic AMP accumulation in He La cells transfected with 5-HT1B or 5-HT1D human receptors. In this model, almotriptan had the same efficacy as serotonin and an affinity in the low n anomolar range. It induced vasoconstriction in several vessels in which it was compared with sumatriptan. In isolated dog saphenous veins, almotriptan elicited concentration-dependent contractions with an EC50 of 394 nM. In b oth these systems, almotriptan behaved as a full agonist. Infusion of almot riptan into the porcine meningeal vasculature induced vasoconstriction. In contrast, in the pig renal and rabbit mesenteric arteries, it had a very lo w maximal efficacy even at 100 muM, with similar results obtained in the ra bbit renal artery. The results suggest that almotriptan is a potent and sel ective 5-HT1B/1D receptor agonist, with selectivity for the cranial vascula ture as compared with peripheral vessels. (C) 2000 Elsevier Science B.V. Al l rights reserved.