Prokai Laszlo, Prokai-Tatrai Katalin, Zharikova Alevtina D, Nguyen Vien, Perjesi Pal, Stevens Stanley M
Department of Medicinal Chemistry, Department of Pharmacology and Therapeutics, and The McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
J Med Chem. 2004 Nov 18;47(24):6025-33. doi: 10.1021/jm020531t.
Metabolically stable and centrally acting thyrotropin-releasing hormone (TRH) analogues were designed by replacing the central histidine with substituted pyridinium moieties. Their analeptic and acetylcholine-releasing actions were evaluated to assess their potency as central nervous system (CNS) agents. A strong experimental connection between these two CNS-mediated actions of the TRH analogues was obtained in subject animals. The analogue 3-(aminocarbonyl)-1-(3-[2-(aminocarbonyl)pyrrolidin-1-yl]-3-oxo-2-[[(5-oxopyrrolidin-2-yl)carbonyl]amino]propyl)pyridinium (1a) showed the highest (TRH-equivalent) potency and longest, dose-dependent duration of action from a series of homologous compounds in antagonizing pentobarbital-induced narcosis when administered intravenously in its CNS-permeable prodrug form (2a) obtained via reduction of the pyridinium moiety to the nonionic dihydropyridine. The maximum change in hippocampal acetylcholine concentration upon perfusion of the pyridinium-containing tripeptides into the hippocampus of rats was also achieved with 1a. No binding to the endocrine TRH receptor was measured for the TRH analogues reported here; therefore, our design afforded a novel lead for centrally acting TRH analogues. We have also demonstrated the benefits of the prodrug approach on the pharmacokinetics and brain uptake/retention of pyridinium-containing TRH analogues (measured by in vivo microdialysis sampling) upon systemic administration.
通过用取代的吡啶鎓部分取代中心组氨酸，设计出了代谢稳定且具有中枢作用的促甲状腺激素释放激素（TRH）类似物。对它们的兴奋作用和乙酰胆碱释放作用进行了评估，以评估其作为中枢神经系统（CNS）药物的效力。在受试动物中，获得了TRH类似物的这两种CNS介导作用之间的紧密实验联系。类似物3-(氨基甲酰基)-1-(3-[2-(氨基甲酰基)吡咯烷-1-基]-3-氧代-2-[[(5-氧代吡咯烷-2-基)羰基]氨基]丙基)吡啶鎓（1a）在以其可透过CNS的前药形式（通过将吡啶鎓部分还原为非离子二氢吡啶获得）静脉给药时，在拮抗戊巴比妥诱导的麻醉方面，显示出一系列同源化合物中最高的（与TRH等效的）效力和最长的、剂量依赖性的作用持续时间。在用含吡啶鎓的三肽灌注大鼠海马体时，1a也实现了海马体乙酰胆碱浓度的最大变化。本文报道的TRH类似物未检测到与内分泌TRH受体的结合；因此，我们的设计为具有中枢作用的TRH类似物提供了一种新的先导化合物。我们还证明了前药方法对含吡啶鎓的TRH类似物全身给药后的药代动力学以及脑摄取/保留（通过体内微透析采样测量）的益处。
