Prokai-Tatrai K, Teixido M, Nguyen V, Zharikova A D, Prokai L
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1600 Archer Road, Gainesville, FL 32610-0485, USA.
Med Chem. 2005 Mar;1(2):141-52. doi: 10.2174/1573406053175256.
A metabolically stable and centrally acting analog of pGlu-Glu-Pro-NH2 ([Glu2]TRH, a tripeptide structurally related to TRH (thyrotropin-releasing hormone)) was designed by replacing the amino-terminal pyroglutamyl residue with a pyridinium moiety. The analeptic action of the analog was used to optimize the efficacy of this novel CNS agent when administered intravenously in its CNS-permeable prodrug forms obtained via the reduction of the pyridinium moiety to the nonionic dihydropyridine and esterifying the central Glu with various alcohols. The maximum effect in antagonizing pentobarbital-induced narcosis in mice was achieved with the hexyl ester that was used subsequently for a comparative evaluation with a prodrug of the parent neuropeptide in the Porsolt swim test as a paradigm for antidepressant effect. The novel analog maintained its antidepressant potency but showed reduced analeptic action compared to [Glu2]TRH; thus, an increase in the selectivity of CNS-action was obtained by the incorporation of the pyridinium moiety.
通过用吡啶鎓部分取代氨基末端焦谷氨酰残基，设计了一种代谢稳定且具有中枢作用的pGlu-Glu-Pro-NH2类似物（[Glu2]TRH，一种与促甲状腺激素释放激素（TRH）结构相关的三肽）。当以通过将吡啶鎓部分还原为非离子二氢吡啶并将中心谷氨酸与各种醇酯化而获得的可透过中枢神经系统的前药形式静脉给药时，该类似物的兴奋作用被用于优化这种新型中枢神经系统药物的疗效。在小鼠中拮抗戊巴比妥诱导的麻醉的最大效果是用己酯实现的，随后在作为抗抑郁作用范例的Porsolt游泳试验中，将其用于与母体神经肽的前药进行比较评估。与[Glu2]TRH相比，这种新型类似物保持了其抗抑郁效力，但显示出较弱的兴奋作用；因此，通过引入吡啶鎓部分提高了中枢神经系统作用的选择性。
