Brain receptor binding characteristics and pharmacokinetics of JTP-2942, anovel thyrotropin-releasing hormone (TRH) analogue

JTP-2942 competed with [H-3]-Me-TRH for the binding sites in rat brain in v itro, 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 [H-3]-Me-TRH binding. Intravenous injection of JTP-2942 (0.3-3 m g/kg) and TRH (3 and 10 mg/kg) produced a significant reduction of [H-3]-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 l east 3 times more potent than that of TRH in decreasing Bmax values for bra in [H-3]-Me-TRH binding. Plasma concentration of JTP-2942 (0.3-3 mg/kg) aft er intravenous injection in rats rose with the increase of dose, and it pea ked immediately after the injection, thereafter decreasing with t(1/2) of 1 9.3-29.9 min. It is concluded that JTP-2942, compared to TRH, may exert fai rly potent and sustained occupation of brain TRH receptors under in vivo co ndition. Thus, JTP-2942 could be clinically useful for the treatment of CNS disorders.