Enaminone amides as novel orally active GABAA receptor modulators.
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.
Hogenkamp
Derk J
DJ
Department of Pharmacology, School of Medicine, Med Surge 2, University of California-Irvine, Irvine, California 92697, USA. dhogenka@uci.edu
Johnstone
Timothy B C
TB
Huang
Jin-Cheng
JC
Li
Wen-Yen
WY
Tran
Minhtam
M
Whittemore
Edward R
ER
Bagnera
Rudy E
RE
Gee
Kelvin W
KW
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
D000577:Amides; D011963:Receptors, GABA-A