NOVEL 2-SUBSTITUTED TETRAHYDRO-3H-BENZ[E]INDOLAMINES - HIGHLY POTENT AND SELECTIVE AGONISTS ACTING AT THE 5-HT(1A) RECEPTOR AS POSSIBLE ANXIOLYTICS AND ANTIDEPRESSANTS

The synthesis of propyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole [( R)-14, U92016A], a potent 5-HT1A agonist, and related analogs is descr ibed. In vitro binding studies show that the (R)-enantiomers of this s eries possess the highest potency for the 5-HT1A receptor. In vivo hyp othermia correlates with this, with the (R)-enantiomers causing a grea ter temperature drop than the (S)-enantiomers. The most active compoun d in 5-HT1A binding and in the tn vivo models was (R) - 14, which was found to be highly potent as an agonist in single cell firing studies, as well as potent and of very high intrinsic activity in mouse hypoth ermia and the sympathetic nerve discharge (SND) models. An in vivo dur ation of action study, following SND, showed (R)-14 to possess a long duration of action. The synthesis via a nitrene insertion, determinati on of absolute configuration, and biological activities of this series is described.