Department of Medicinal Chemistry , The University of Kansas , Lawrence , Kansas 66045 , United States.
Biotechnology Innovation and Optimization Center , The University of Kansas , Lawrence , Kansas 66045 , United States.
ACS Chem Neurosci. 2018 Jul 18;9(7):1735-1742. doi: 10.1021/acschemneuro.8b00085. Epub 2018 Apr 19.
Opioid peptides are key regulators in cellular and intercellular physiological responses, and could be therapeutically useful for modulating several pathological conditions. Unfortunately, the use of peptide-based agonists to target centrally located opioid receptors is limited by poor physicochemical (PC), distribution, metabolic, and pharmacokinetic (DMPK) properties that restrict penetration across the blood-brain barrier via passive diffusion. To address these problems, the present paper exploits fluorinated peptidomimetics to simultaneously modify PC and DMPK properties, thus facilitating entry into the central nervous system. As an initial example, the present paper exploited the Tyr-ψ[( Z)CF═CH]-Gly peptidomimetic to improve PC druglike characteristics (computational), plasma and microsomal degradation, and systemic and CNS distribution of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Thus, the fluoroalkene replacement transformed an instable in vitro tool compound into a stable and centrally distributed in vivo probe. In contrast, the Tyr-ψ[CFCH-NH]-Gly peptidomimetic decreased stability by accelerating proteolysis at the Gly-Phe position.
阿片肽是细胞和细胞间生理反应的关键调节剂，对于调节多种病理状况可能具有治疗作用。不幸的是，基于肽的激动剂用于靶向中枢定位的阿片受体受到较差的理化（PC）、分布、代谢和药代动力学（DMPK）特性的限制，这些特性限制了通过被动扩散穿透血脑屏障。为了解决这些问题，本文利用氟化肽模拟物来同时修饰 PC 和 DMPK 特性，从而促进进入中枢神经系统。作为一个初步的例子，本文利用 Tyr-ψ[(Z)CF=CH]-Gly 肽模拟物来改善 PC 类药性特征（计算）、血浆和微粒体降解以及亮啡肽（Tyr-Gly-Gly-Phe-Leu）的全身和中枢神经系统分布。因此，氟烯的替代将不稳定的体外工具化合物转化为稳定的和中枢分布的体内探针。相比之下，Tyr-ψ[CFCH-NH]-Gly 肽模拟物通过加速 Gly-Phe 位置的蛋白水解来降低稳定性。
