C-9 and N-Substituted Analogs of cis-(3aR)-(-)-2,3,3a,4,5,9b-Hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide: 5-HT1A Receptor Agonists with Various Degrees of Metabolic Stability

Closely related analogs of the 5-HT1A receptor agonist cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9- carboxamide (1, U93385) were synthesized and pharmacologically evaluated. 9-Carboxamide analogs with varied nitrogen substitution (R2) were synthesized, and their serotonergic activity was evaluated in vitro and in vivo. Many of these compounds were incubated in the presence of rat hepatocytes, and the metabolic stability in vitro was compared to that of compound 1. Only the N-methyl and N-ethyl analogs ((-)-5a and (-)-5b) were more stable than compound 1, indicating that N-dealkylation is a major route of metabolism in this series. In addition, these analogs were found to be partial 5-HT1A receptor agonists in vivo. Modifications were also made to the carboxamide functionality of compound 1 (R1 in 2) to yield substituted amides or ketones. Among these analogs, the methyl ketone (-)-15a was found to be a 5-HT1A agonist with full intrinsic activity in vivo and was approximately 20 times more potent than compound 1 and 5 times more potent than 8-OH-DPAT.