Design and exploratory neuropharmacological evaluation of novel thyrotropin-releasing hormone analogs and their brain-targeting bioprecursor prodrugs.
Design and exploratory neuropharmacological evaluation of novel thyrotropin-releasing hormone analogs and their brain-targeting bioprecursor prodrugs.
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DOI：
10.3390/pharmaceutics5020318
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发表时间：
2013-01-01
期刊：
影响因子：
5.4
通讯作者：
Prokai, Laszlo
中科院分区：
文献类型：
--
作者：
Prokai-Tatrai, Katalin;Nguyen, Vien;Prokai, Laszlo
利用大脑中促甲状腺素释放激素（TRH）的有益活性的努力受到其代谢稳定性差和缺乏足够的中枢神经系统生物利用度的阻碍。我们在此报告了新型且代谢稳定的类似物，这些类似物是通过用含吡啶部分取代 TRH 的氨基末端焦谷氨酰 (pGlu) 残基而衍生的。探索性研究表明，所得化合物通过其生物前体前药全身给药后成功递送至小鼠大脑，并表现出内源性母肽特征的神经药理学反应。另一方面，当 pGlu 被葫芦巴酰残基取代时，在测试抗抑郁样作用并同时保留兴奋活性的模型中，观察到与 TRH 相比效力的损失。这一发现可能表明有机会设计对胆碱能效应具有潜在选择性的 TRH 类似物。
Efforts to take advantage of the beneficial activities of thyrotropin-releasing hormone (TRH) in the brain are hampered by its poor metabolic stability and lack of adequate central nervous system bioavailability. We report here novel and metabolically stable analogs that we derived from TRH by replacing its amino-terminal pyroglutamyl (pGlu) residue with pyridinium-containing moieties. Exploratory studies have shown that the resultant compounds were successfully delivered into the mouse brain after systemic administration via their bioprecursor prodrugs, where they manifested neuropharmacological responses characteristic of the endogenous parent peptide. On the other hand, the loss of potency compared to TRH in a model testing antidepressant-like effect with a simultaneous preservation of analeptic activity has been observed, when pGlu was replaced with trigonelloyl residue. This finding may indicate an opportunity for designing TRH analogs with potential selectivity towards cholinergic effects.