The chemical evolution of N,N-dimethyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethylamine (L-741,604) and analogues: Potent and selective agonists for 5-HT 1D receptors

Abstract

Optimisation of a series of 5-(heterocyclyl)tryptamines led to the identification of the symmetrically substituted, N-4 linked 1,2,4-triazole as the best indole C-5 substituent for 5-HT 1D receptor affinity and selectivity. The triazole ( 8) is the most potent and selective, orally bioavailable, 5-HT 1D receptor agonist identified to date, showing an order of magnitude greater potency than the clinical compound sumatriptan with improved subtype selectivity.