CGS 20625, a novel pyrazolopyridine anxiolytic.
CGS 20625 (2-(4-methoxyphenyl)2,3,5,6,7,8,9,10-octa hydrocyclohepta[b]pyrazolo-[3,4-d]pyridin-3-one) is a potent and selective ligand for the central benzodiazepine receptor (IC50 = 1.3 nM), with little or no affinity to several other neurotransmitter receptor binding sites in vitro. CGS 20625 had a gamma-aminobutyric acid ratio of 0.9 and increased t-[35S]butylbicyclophosphorothionate binding by 20% in vitro, a profile indicative of a partial agonist or mixed agonist/antagonist. In vivo, CGS 20625 blocked a pentylenetetrazol discriminative cue with an ED50 = 1.7 mg/kg p.o. The compound selectively increased conflict responding in the Cook-Davidson paradigm with a minimal effective dose of 0.3 mg/kg p.o., as compared with 3.0 mg/kg p.o. for diazepam. At doses as high as 100 mg/kg p.o., CGS 20625 had no effect on variable interval responding, suggesting minimal sedation. Unlike diazepam, CGS 20625 had no effect on rotorod performance at doses up to 100 mg/kg p.o. indicating no overt muscle relaxation, and did not potentiate the action of ethanol in this behavioral paradigm. Also, CGS 20625 had no marked effect on locomotor behavior, did not potentiate hexobarbital sleep time and had no sedative activity at doses up to 300 mg/kg p.o. CGS 20625 was efficacious in preventing pentylenetetrazol-induced seizures (ED50 = 0.7 mg/kg p.o.), had less efficacy with no clear dose-response relationship against picrotoxin-induced seizures and had no effect on either strychnine or electroshock-induced convulsions at doses up to 300 mg/kg p.o.(ABSTRACT TRUNCATED AT 250 WORDS)
Williams
M
M
Research Department, Ciba-Geigy Corporation, Summit, New Jersey.
Bennett
D A
DA
Loo
P S
PS
Braunwalder
A F
AF
Amrick
C L
CL
Wilson
D E
DE
Thompson
T N
TN
Schmutz
M
M
Yokoyoma
N
N
Wasley
J W
JW
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D011720:Pyrazoles; D011949:Receptors, Cholecystokinin; D011963:Receptors, GABA-A; C054732:CGS 20625; D003975:Diazepam