The anxioselective agent 7-(2-chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) is more efficacious than diazepam at enhancing GABA-gated currents at alpha1 subunit-containing GABAA receptors.
Studies using mice with point mutations of GABA(A) receptor alpha subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA(A) receptors bearing the alpha(1) and alpha(2) subunits. This hypothesis predicts that a compound with high efficacy at GABA(A) receptors containing the alpha(1) subunit would produce sedation, whereas an agonist acting at alpha(2) subunit-containing receptors (with low or null efficacy at alpha(1)-containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA(A) receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at alpha(1)beta(2)gamma(2S) constructs of the GABA(A) receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing alpha(2), alpha(3), or alpha(5) subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test, an effect blocked by flumazenil, and increased the percentage of time spent in the open arms of the elevated plus-maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than 1 order of magnitude greater than the minimal effective anxiolytic dose. Although the mutant mouse data predict that the high-efficacy potentiation of GABA(A1a) receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by alpha(1) subunit-containing GABA(A) receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.
Popik
Piotr
P
Behavioral Neuroscience, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Kostakis
Emmanuel
E
Krawczyk
Martyna
M
Nowak
Gabriel
G
Szewczyk
Bernadeta
B
Krieter
Philip
P
Chen
Zhengming
Z
Russek
Shelley J
SJ
Gibbs
Terrell T
TT
Farb
David H
DH
Skolnick
Phil
P
Lippa
Arnold S
AS
Basile
Anthony S
AS
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001259:Ataxia / Q000139:chemically induced / Q000473:pathology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D018737:Hand Strength / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D004856:Postural Balance / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
C515926:7-(2-chloropyridin-4-yl)pyrazolo-(1,5-a)-(pyrimidin-3-yl)(pyridin-2-yl)methanone; D014151:Anti-Anxiety Agents; D018118:Chloride Channels; D006993:Hypnotics and Sedatives; D011720:Pyrazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D003975:Diazepam