Enaminone Amides as Novel Orally Active GABAA Receptor Modulators

• Published in: Journal of medicinal chemistry 2007-07, Vol.50 (14), p.3369-3379
• Main Authors: Hogenkamp, Derk J, Johnstone, Timothy B. C, Huang, Jin-Cheng, Li, Wen-Yen, Tran, Minhtam, Whittemore, Edward R, Bagnera, Rudy E, Gee, Kelvin W
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amides - pharmacology; Animals; Biological and medical sciences; Gabaergic and benzodiazepinic system; Magnetic Resonance Spectroscopy; Male; Medical sciences; Mice; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070083v

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.