title: Agonist and antagonist activities at benzodiazepine receptors of a novel series of quinoline derivatives.
abstract: Five members of a novel series of quinoline derivatives which all have similar activities on benzodiazepine receptor binding in vitro were compared in a food-motivated conflict and stress-induced ultrasounds models of anxiety and on suprahyoid muscle twitching in urethane-anaesthetised rats. RU 42382, RU 43028 and RU 39419 showed anxiolytic activity in both tests and RU 40410 was an antagonist. RU 40744 inhibited stress-induced ultrasounds but had little activity in the conflict test. Amphetamine-induced suprahyoid muscle twitching was only weakly inhibited by RU 42382 and RU 43028 in comparison with a classical benzodiazepine agonist. Ro15-1788 antagonised RU 42382 indicating that a major component of its action was agonism at benzodiazepine receptors. RU 39419 had no effect, RU 40744 tended to increase and RU 40410 evoked a small but statistically significant increase in twitching. The same rank order was observed in antagonism of a benzodiazepine in the muscle twitching model. RU 42382 was least effective as an antagonist and RU 40410 most effective. RU 39419 had no effect alone but antagonised the decrease of firing rate of cerebellar Purkinje cells induced by a benzodiazepine in urethane-anaesthetised rats. Comparison of in vivo occupancy of benzodiazepine receptors and efficacy in the conflict test in rats suggests a ranking of agonist intrinsic activity: RU 42382 greater than RU 43028 greater than RU 39419. A simple relationship between intrinsic activity at benzodiazepine receptors and structure of the compounds is proposed.
authors.affiliation: Roussel Laboratories Limited, Covingham, Swindon, Wiltshire, U.K.
authors.forename: C R
authors.initials: CR
authors.lastname: Gardner
authors.forename: R
authors.initials: R
authors.lastname: Deacon
authors.forename: V
authors.initials: V
authors.lastname: James
authors.forename: F
authors.initials: F
authors.lastname: Parker
authors.forename: P
authors.initials: P
authors.lastname: Budhram
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003220:Conflict, Psychological; D008297:Male; D011689:Purkinje Cells / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013035:Spasm / Q000139:chemically induced; D013312:Stress, Physiological / Q000503:physiopathology
chemical_list: D011804:Quinolines; D011963:Receptors, GABA-A