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

Article abstract of DOI:10.1021/jm00046a010

Derivatives and isosteric derivatives of the potent 5-HT_1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benzindole-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 1-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives.The isosteric 6,7,8,9-tetrahydro-1H-benzindoles 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 5-HT_1A subtype are discussed.Compounds 6 and 8 were found to have high oral bioavailability in the rat (63percent and 54percent, respectively).