Yamamura M, Suzuki M, Matsumoto K
Pharmaceutical Development Research Laboratory, Saitama, Japan.
Nihon Yakurigaku Zasshi. 1997 Oct;110 Suppl 1:33P-38P. doi: 10.1254/fpj.110.supplement_33.
Taltirelin hydrate[1-methyl-(S)-4,5-dihydroorotyl-L-histidyl-L-prolineamide tetrahydrate] is a new orally active thyrotropin releasing hormone (TRH) peptide analog synthetized from aspartic acid. From preclinical studies with mice and rats, Taltirelin hydrate was found to be highly stable in the blood and brain as compared with TRH. Furthermore, the CNS stimulating actions of Taltirelin hydrate such as antagonistic actions against pentobarbital-induced anesthesia and reserpine- induced hypothermia were found to be about 100 times stronger and about 8 times longer-lasting as compared with those of TRH. Meanwhile, the affinity of Taltirelin hydrate for TRH-receptors was about 10 times lower, and the endocrine action was about 5 times less potent than those of TRH. Therefore, high CNS-selectivity and long-lasting action of Taltirelin hydrate would be attributed to its high stability in the body and low affinity for TRH-receptors. Oral administrations of Taltirelin hydrate ameliorated consiousness impairment, memory impairment and motor dysfunction in several models. The clinical studies for patients with spinocerebellar degeneration are in progress.
水合他替瑞林[1-甲基-(S)-4,5-二氢乳清酰-L-组氨酰-L-脯氨酰胺四水合物]是一种新的口服活性促甲状腺激素释放激素（TRH）肽类似物，由天冬氨酸合成。通过对小鼠和大鼠的临床前研究发现，与TRH相比，水合他替瑞林在血液和大脑中具有高度稳定性。此外，发现水合他替瑞林的中枢神经系统刺激作用，如对戊巴比妥诱导的麻醉和利血平诱导的体温过低的拮抗作用，与TRH相比约强100倍，持续时间约长8倍。同时，水合他替瑞林对TRH受体的亲和力约低10倍，内分泌作用比TRH弱约5倍。因此，水合他替瑞林的高中枢神经系统选择性和长效作用归因于其在体内的高稳定性和对TRH受体的低亲和力。在几种模型中，口服水合他替瑞林可改善意识障碍、记忆障碍和运动功能障碍。针对脊髓小脑变性患者的临床研究正在进行中。
