Binding of Tetrahydrocarboline Derivatives at Human 5-HT5AReceptors

Publisher Website
Google Scholar
Abstract
On the basis of an earlier finding that 5-methyl-5H-1,2,3,4-tetrahydropyrido[4,3-b]indole (5-methyl-1,2,3,4-tetrahydro-γ-carboline; 1) binds at murine 5-HT5A receptors, preliminary structure−affinity studies were conducted. The present investigation extends these structure−affinity studies using human 5-HT5A receptors and examined additional analogues of 1. It was found (a) that there is little interspecies difference for the affinities of these compounds, (b) that an intact 1,2,3,4-tetrahydro-γ-carboline ring system seems optimal and an N2-(3-(substituted-phenoxy)propyl) moiety results in high affinity, (c) that structurally related 1,2,3,4-tetrahydro-β-carbolines also bind at 5-HT5A receptors, and (d) that all examined derivatives also possess affinity for 5-HT2A receptors. Evidence is provided that 5-HT5A and 5-HT2A receptor affinities probably do not covary and that it might be possible, with continued investigation, to develop analogues with enhanced 5-HT5A selectivity.