The central nervous system (CNS) effects of a novel thyrotropin-releasing hormone (TRH) analogue, JTP-2942 (Na-alpha- ((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-pro linamide monohydrate, CAS 131404-34-7) were investigated and compared with those of TRH. When administrated subcutaneously, JTP-2942 was about 80 times more potent than TRH in the antagonization of reserpine-induced hypothermia, and when administrated intravenously it was about 16 times more potent than TRH in the potentiation of flexor reflexes. Furthermore, oral administration of JTP-2942 was able to antagonize a chlorpromazine-induced reduction in locomotor activity, while TRH was far less effective. In tests on the recovery from pentobarbital-induced sleep and disturbance of consciousness induced by concussive head trauma, JTP-2942 was about 30 and 3 times more potent than TRH, respectively. Thus, JTP-2942 had a far stronger and more persistent action compared with TRH in regard to these effects. However, JTP-2942 had a 3-fold lower effect on thyroid stimulating hormone (TSH) release than TRH. These results suggest that the stimulatory effects of JTP-2942 are selective for the CNS and that this TRH analogue may be applicable to clinical use.