Synthesis and serotonergic activity of 2-oxadiazolyl-5-substituted-N,N-dimethyltryptamines: novel antagonists for the vascular 5-HT1B-like receptor

Abstract

The synthesis and vascular 5-HT_1B-like receptor activity of a novel series of 2-oxadiazolyl-5-substituted tryptamine derivatives 2 is described. Modifications to the 2-oxadiazolyl group R¹, the heterocycle R² 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 particular, 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 α₁-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.