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

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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Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.


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.

[Indexed for MEDLINE]

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