6,7,8,9-TETRAHYDRO-N,N-DI-N-PROPYL-3H-BENZINDOL-8-AMINES - DERIVATIVES AS POTENT AND ORALLY-ACTIVE SEROTONIN 5-HT1A RECEPTOR AGONISTS

Abstract

Derivatives and isosteric derivatives of the potent 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole- 1-carbaldehyde (5) were prepared and evaluated in vivo and in vitro for serotonergic and dopaminergic activity. The 1-cyano analog 8 was found to be almost equipotent to 5 and the previously described 2-cyano derivative 6, while a I-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives. The isosteric 6,7,8,9-tetrahydro-1H-benz[g]indoles 4 and 12-15 showed surprisingly low affinity or activity at both serotonergic and dopaminergic systems. The interpretations of these results by means of drug-receptor interactions at the 5-HT1A subtype are discussed. Compounds 6 and 8 were found to have high oral bioavailability in the rat (63% and 54%, respectively)