Enaminone Amides as Novel Orally Active GABA sub(A) Receptor Modulators

A series of enaminone esters and amides have been developed as potent allosteric modulators of gamma -aminobutyric acid sub(A) (GABA sub(A)) receptors. The compounds bind to a novel modulatory site that is independent of the benzodiazepine (BZ), isosteric GABA, and neuroactive steroid binding sites....

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Published in:Journal of medicinal chemistry 2007-07, Vol.50 (14), p.3369-3379
Main Authors: Hogenkamp, D J, Johnstone, TBC, Huang, J-C, Li, W-Y, Tran, M, Whittemore, E R, Bagnera, R E, Gee, K W
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container_end_page 3379
container_issue 14
container_start_page 3369
container_title Journal of medicinal chemistry
container_volume 50
creator Hogenkamp, D J
Johnstone, TBC
Huang, J-C
Li, W-Y
Tran, M
Whittemore, E R
Bagnera, R E
Gee, K W
description A series of enaminone esters and amides have been developed as potent allosteric modulators of gamma -aminobutyric acid sub(A) (GABA sub(A)) receptors. The compounds bind to a novel modulatory site that is independent of the benzodiazepine (BZ), isosteric GABA, and neuroactive steroid binding sites. Structure-activity relationship (SAR) studies resulted in the synthesis of the c-Bu amide 16h with an in vitro potency of 7 nM based on inhibition of [ super(35)S]TBPS binding. The activity of the enaminones as positive allosteric modulators was confirmed with electrophysiological measurements in oocytes expressing alpha sub(1) beta sub(2) gamma sub(2L) GABA sub(A) receptors. The i-Pr, s-Bu, c-Pr, and c-Bu amides (16e-h) were orally active in mice with profound central nervous system depressant effects. The i-Pr amide 16e was an orally active anxiolytic in the mouse light-dark paradigm.
doi_str_mv 10.1021/jm070083v
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title Enaminone Amides as Novel Orally Active GABA sub(A) Receptor Modulators
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