The behavioural properties of CI-988, a selective cholecystokininB receptor antagonist.
1. The behavioural effects of a selective cholecystokininB (CCKB) receptor antagonist CI-988 were investigated in rodents. 2. In three rodent tests of anxiety (rat elevated X-maze, rat social interaction test and mouse light/dark box) CI-988 over the dose range 0.001-10.0 mg kg-1, (i.p.) produced an anxiolytic-like action. The magnitude of this effect was similar to that of chlordiazepoxide (CDP). In contrast, the selective CCKA receptor antagonist, devazepide, was inactive. CI-988 also showed anxiolytic-like action in the rat conflict test but the magnitude of this effect was about 2.5 fold less than that of CDP. 3. Central but not peripheral administration of the selective CCKB receptor agonist, pentagastrin, like FG 7142, produced an anxiogenic-like action. 4. The pentagastrin-induced anxiety was dose-dependently antagonized by CI-988, whereas devazepide was inactive. However, ten times higher doses of CI-988 were required to block a similar action of FG 7142. 5. In contrast to CDP, CI-988 up to 3000 fold higher doses than those inducing anxiolysis was inactive in tests measuring sedation and ataxia. It also failed to antagonize pentylenetetrazol-induced tonic seizures. Furthermore, CI-988 did not interact with alcohol or barbiturates. Thus, CI-988 appears to be an anxioselective compound. 6. The anxiolytic-like action of CDP in the rat elevated X-maze was dose-dependently antagonized by flumazenil. In contrast, the benzodiazepine receptor antagonist failed to block a similar effect of CI-988. 7. Thus, CI-988 shows anxiolytic-like activity in several animal models of anxiety. The anxiolytic-like effect of CI-988 involves a novel mechanism of action, that is likely to be mediated by selective antagonism of the brain CCKB receptor. It is suggested that CI-988 should have a better side-effect profile in man than the benzodiazepines.
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge.
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Singh
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Field
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Hughes
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Menzies
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Oles
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Vass
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Woodruff
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001570:Benzodiazepinones / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors; D003220:Conflict, Psychological; D020109:Devazepide; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010418:Pentagastrin / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012919:Social Behavior
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001570:Benzodiazepinones; D002243:Carbolines; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D007211:Indoles; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C058121:L 365260; D000431:Ethanol; C035874:FG 7142; D008536:Meglumine; D002766:Cholecystokinin; D010418:Pentagastrin; D010424:Pentobarbital; D020109:Devazepide; D010433:Pentylenetetrazole