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

2000; Elsevier BV; Volume: 410; Issue: 1 Linguagem: Inglês

10.1016/s0014-2999(00)00876-1

1879-0712

Josep Bou, Teresa Domènech, Jaume Puig, Ascensión Heredia, Jordi Gras, Dolors Fernández‐Forner, Jörge Beleta, J.M. Palacios,

Nitric Oxide and Endothelin Effects

Almotriptan (3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole) has been studied in several models predictive of activity and selectivity at 5-HT receptors. Almotriptan showed low nanomolar affinity for the 5-HT1B and 5-HT1D receptors in several species, including the human, while affinity for 5-HT receptors other than 5-HT1B/1D was clearly less. Affinity 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 exhibit significant affinity for several non-5-HT receptors studied up to 100 μM. Almotriptan inhibited forskolin-stimulated cyclic AMP accumulation in HeLa 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 nanomolar 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 both these systems, almotriptan behaved as a full agonist. Infusion of almotriptan into the porcine meningeal vasculature induced vasoconstriction. In contrast, in the pig renal and rabbit mesenteric arteries, it had a very low maximal efficacy even at 100 μM, with similar results obtained in the rabbit renal artery. The results suggest that almotriptan is a potent and selective 5-HT1B/1D receptor agonist, with selectivity for the cranial vasculature as compared with peripheral vessels.