Synthesis and serotonergic activity of 2-oxadiazolyl-5-substituted-N, N-dimethyltryptamines: novel antagonists for the vascular 5-HT_(1B)-like receptor

摘要

The synthesis and vascular 5-HT_(1B)-like receptor activity of a novel series of 2-oxadiazolyl-t-substituted tryptamine derivatives 2 is described. Modifications to the 2-oxadiazolyl group R~1, the heterocycle R~2 and the length of the linking chain (n) have been explored. Several compounds were identified which exhibited moderate 5-HT_(1B)-like receptor affinity. In particualr, 2-(3-ethyl-1, 2, 4-oxadiazol-5-yl)-3-[2-(dimethylamino)ethyl]-5-[(4, 4-dimethyl-2, 5-dioxoimidazolidin-1-yl)methyl]-1H-indole (20) in which n = 1 had a pK_B = 7.23 at the 5-HT_(1B)-like receptor and > 60 fold selectivity over #alpha#_1-adrenoceptor affinity. This contrasts with the higher homologue derivatives such as 10 and 11 where n = 2 which exhibited decreased potency and selectivity for the 5-HT_(1B)-like receptor. The 2-oxadiazolyl-5-substituted-N, N-dimethyltryptamine derivatives were found to be silent (as judged by the inability of angiotensin II to unmask 5-HT_(1B)-like receptor mediated agonist activity in the rabbit femoral artery) and competitive 5-HT_(1B)-like receptor antagonists with half lives of up to 1.5 hours in dog plasma and with good oral bioavailability.