Enaminone Amides as Novel Orally Active GABAA Receptor Modulators

A series of enaminone esters and amides have been developed as potent allosteric modulators of γ-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 α1β2γ2L 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.