Novel 2-substituted tetrahydro-3H-benz[e]indolamines: highly potent and selective agonists acting at the 5-HT1A receptor as possible anxiolytics and antidepressants.

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Romero AG, Leiby JA, McCall RB, Piercey MF, Smith MW, Han F

Novel 2-substituted tetrahydro-3H-benz[e]indolamines: highly potent and selective agonists acting at the 5-HT1A receptor as possible anxiolytics and antidepressants.

J Med Chem. 1993 Jul 23;36(15):2066-74.

PubMed ID

8101876 [ View in PubMed

]

Abstract

The synthesis of (+)-(R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H- benz[e]indole [(R)-14, U92016A], a potent 5-HT1A agonist, and related analogs is described. In vitro binding studies show that the (R)-enantiomers of this series possess the highest potency for the 5-HT1A receptor. In vivo hypothermia correlates with this, with the (R)-enantiomers causing a greater temperature drop than the (S)-enantiomers. The most active compound in 5-HT1A binding and in the in 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 hypothermia and the sympathetic nerve discharge (SND) models. An in vivo duration of action study, following SND, showed (R)-14 to possess a long duration of action. The synthesis via a nitrene insertion, determination of absolute configuration, and biological activities of this series is described.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Buspirone	5-hydroxytryptamine receptor 1A	Ki (nM)	3.1	N/A	N/A	Details
Buspirone	Dopamine D2 receptor	Ki (nM)	13	N/A	N/A	Details