STRUCTURE-ACTIVITY-RELATIONSHIPS IN THE 8-AMINO-6,7,8,9-TETRAHYDRO-3H-BENZ[E]INDOLE RING-SYSTEM .1. EFFECTS OF SUBSTITUENTS IN THE AROMATIC SYSTEM ON SEROTONIN AND DOPAMINE-RECEPTOR SUBTYPES

A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A agonist 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D-2, and D-3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but-many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.