SYNTHESIS AND SEROTONERGIC ACTIVITY OF HYL-2-[5-(1,2,4-TRIAZOL-1-YLMETHYL)-1H-INDOL-3-YL] ETHYLAMINE AND ANALOGS - POTENT AGONISTS FOR 5-HT1D RECEPTORS

The synthesis and the 5-HT receptor activity of a novel series of N,N- dimethyltryptamines substituted in the 5-position with an imidazole, t riazole, or tetrazole ring are described. The objective of this work w as to identify potent and selective 5-HT1D receptor agonists with high oral bioavailability and low central nervous system penetration. Comp ounds have been prepared in which the azole ring is attached through e ither nitrogen or carbon to the indole. Conjugated and methylene-bridg ed derivatives have been studied (n = 0 or 1). Substitution of the azo le ring has been explored either alpha or beta to the point of attachm ent to indole. In a series of N-linked azoles (X = N), simple unsubsti tuted compounds have high affinity and selectivity for 5-HT1D receptor s. It is proposed that for good affinity and selectivity a hydrogen bo nd acceptor interaction with the 5-HT1D receptor, through a beta-nitro gen in the azole ring, is required. In a series of C-linked triazoles and tetrazoles (X = C), optimal affinity and selectivity for the 5-HT1 D receptor was observed when the azole ring is substituted at the 1-po sition with a methyl or ethyl group. This study has led to the discove ry of the 1,2,4-triazole 10a (MK-462) as a potent and selective 5-HT1D receptor agonist which has high oral bioavailability and rapid oral a bsorption. The in vitro activity and the preliminary pharmacokinetics of compounds in this series are presented.