title: L-6-ketopiperidine-2-carbonyl-L-leucyl-L-proline amide as a novel thyrotropin releasing hormone analogue with improving effects on impaired central nervous systems functions.
abstract: Psychopharmacological activities of L-6-ketopiperidine-2-carbonyl-L-leucyl-L-proline amide (RGH-2202) were compared with those of the parent peptide, thyrotropin releasing hormone (TRH, L-pyroglutamyl-L-histidyl-L-prolinamide, Pyr-His-Pro amide) in rodents. RGH-2202 caused qualitatively similar effects to TRH in a variety of tests for the activity on the central nervous system. The compound as well as TRH increased the spontaneous motor activity, enhanced the conditioned avoidance response, and antagonized the avoidance suppression by haloperidol and the sleep-inducing effect of pentorbarbital in mice. It was also efficacious against the deficits of consciousness in mice with concussive head injury and the EEG disturbance in rats with basilar artery occlusion. Besides, it antagonized the cycloheximide-or anoxia-induced amnesia and enhanced the habituation of exploratory activity in mice. Biochemically, it enhanced, like TRH, the turnover of norepinephrine and dopamine in the cerebral cortex, nucleus accumbens and striatum of mice and rats, and increased cyclic GMP levels in the cerebellum of rats. In spite of the global similarity between the pharmacological profiles of RGH-2202 and TRH, there were some intriguing differences between them. RGH-2202 was 2-5 times more effective than TRH in improving the deficits of active avoidance performance and retention in mice, while it was weaker than TRH in modifying the haloperidol-induced catalepsy in mice and enhancing the spinal reflexes in rats. Besides, its thyrotropin releasing activity was about 30 times less potent than that of TRH.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Oka
authors.forename: Y
authors.initials: Y
authors.lastname: Ochi
authors.forename: K
authors.initials: K
authors.lastname: Furukawa
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Miura
authors.forename: T
authors.initials: T
authors.lastname: Karasawa
authors.forename: T
authors.initials: T
authors.lastname: Kadokawa
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors; D006259:Craniocerebral Trauma / Q000188:drug therapy; D004569:Electroencephalography; D005106:Exploratory Behavior / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012890:Sleep / Q000187:drug effects; D013268:Stimulation, Chemical; D009435:Synaptic Transmission / Q000187:drug effects; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002492:Central Nervous System Depressants; D013973:Thyrotropin-Releasing Hormone; C055448:posatirelin