Document Report Card
Basic Information
ID: ALA1145429
Journal: J Med Chem
Title: Enaminone amides as novel orally active GABAA receptor modulators.
Authors: Hogenkamp DJ, Johnstone TB, Huang JC, Li WY, Tran M, Whittemore ER, Bagnera RE, Gee KW.
Abstract: A series of enaminone esters and amides have been developed as potent allosteric modulators of gamma-aminobutyric acidA (GABAA) 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 [35S]TBPS binding. The activity of the enaminones as positive allosteric modulators was confirmed with electrophysiological measurements in oocytes expressing alpha1beta2gamma2L GABAA 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.
CiteXplore: 17571865
DOI: 10.1021/jm070083v