title: Brain receptor binding characteristics and pharmacokinetics of JTP-2942, a novel thyrotropin-releasing hormone (TRH) analogue.
abstract: JTP-2942 competed with [3H]-Me-TRH for the binding sites in rat brain in vitro, and its inhibitory effect was approximately 17 times less potent than TRH, as shown by Ki values of 673 and 39.7 nM, respectively. Both JTP-2942 and TRH significantly increased apparent dissociation constant (Kd values) for brain [3H]-Me-TRH binding. Intravenous injection of JTP-2942 (0.3-3 mg/kg) and TRH (3 and 10 mg/kg) produced a significant reduction of [3H]-Me-TRH binding sites (Bmax values) in rat brain. Although the decrease by TRH was maximal 10 min after the injection and declined rapidly with time, the decrease by JTP-2942 (1 and 3 mg/kg) tended to be maximal at 30 min later and it lasted until 120 min. The intravenous injection of JTP-2942 was at least 3 times more potent than that of TRH in decreasing Bmax values for brain [3H]-Me-TRH binding. Plasma concentration of JTP-2942 (0.3-3 mg/kg) after intravenous injection in rats rose with the increase of dose, and it peaked immediately after the injection, thereafter decreasing with t1/2 of 19.3-29.9 min. It is concluded that JTP-2942, compared to TRH, may exert fairly potent and sustained occupation of brain TRH receptors under in vivo condition. Thus, JTP-2942 could be clinically useful for the treatment of CNS disorders.
authors.affiliation: Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Urayama
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Deguchi
authors.forename: R
authors.initials: R
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000378:metabolism*; D013379:Substrate Specificity; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014316:Tritium
chemical_list: D018025:Receptors, Thyrotropin-Releasing Hormone; D014316:Tritium; C080784:JTP 2942; C017528:thyrotropin-releasing hormone, 1-Me-; D013973:Thyrotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid