CGS 20625, a novel pyrazolopyridine anxiolytic
Williams, M.; Bennett, D.A.; Loo, P.S.; Braunwalder, A.F.; Amrick, C.L.; Wilson, D.E.; Thompson, T.N.; Schmutz, M.; Yokoyoma, N.; Wasley, J.W.
Journal of Pharmacology and Experimental Therapeutics 248(1): 89-96
1989
ISSN/ISBN: 0022-3565 PMID: 2563294 Document Number: 339851
CGS 20625 (2-(4-methoxyphenyl)2,3,5,6,7,8,9,10-octa hydrocycloheptabutylbicyclophosphorothionate 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. CGS 20625, which is structurally related to the clinically efficacious anxioselective anxiolytic, CGS 9896, is over 100 times more soluble than CGS 9896 and is correspondingly more bioavailable, with a half-life of 3.9 hr. Because of its apparent lack of sedative, muscle relaxant and ethanol potentiating effects, and its favorable bioavailability, CGS 20625 may have significant advantages in the treatment of both anxiety states and absence-type seizures.