title: Enaminone amides as novel orally active GABAA receptor modulators.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Med Surge 2, University of California-Irvine, Irvine, California 92697, USA. dhogenka@uci.edu
authors.forename: Derk J
authors.initials: DJ
authors.lastname: Hogenkamp
authors.forename: Timothy B C
authors.initials: TB
authors.lastname: Johnstone
authors.forename: Jin-Cheng
authors.initials: JC
authors.lastname: Huang
authors.forename: Wen-Yen
authors.initials: WY
authors.lastname: Li
authors.forename: Minhtam
authors.initials: M
authors.lastname: Tran
authors.forename: Edward R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: Rudy E
authors.initials: RE
authors.lastname: Bagnera
authors.forename: Kelvin W
authors.initials: KW
authors.lastname: Gee
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D011963:Receptors, GABA-A