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 Tyr¹-ψ[(Z)CF═CH]-Gly² 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 Tyr¹-ψ[CF₃CH₂–NH]-Gly² peptidomimetic decreased stability by accelerating proteolysis at the Gly³–Phe⁴ position.

中文翻译：

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Tyr ^1- ψ[（（Z）CF═CH] -Gly ²氟化拟肽改善亮氨酸脑啡肽的分布和代谢特性

阿片肽是细胞和细胞间生理反应的关键调节因子，可能在调节几种病理状况方面具有治疗作用。不幸的是，基于肽的激动剂用于靶向位于中央的阿片样物质受体受到不良的物理化学（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过血脑屏障的渗透。为了解决这些问题，本论文利用氟化肽模拟物同时修饰PC和DMPK特性，从而促进进入中枢神经系统。作为初始示例，本文利用了Tyr ^1- ψ[（Z）CF═CH] -Gly ²拟肽可改善PC药物样特征（计算​​），血浆和微粒体降解，以及亮氨酸脑啡肽（Tyr-Gly-Gly-Phe-Leu）的全身和中枢神经系统分布。因此，氟代烯烃的替代将不稳定的体外工具化合物转变为稳定且集中分布的体内探针。相反，Tyr ^1- ψ[CF ₃ CH ₂ -NH] -Gly ²拟肽通过加速Gly ³ -Phe ⁴位置的蛋白水解作用降低了稳定性。