Design and synthesis of a bivalent ligand to explore the putative heterodimerization of the mu opioid receptor and the chemokine receptor CCR5.
Design and synthesis of a bivalent ligand to explore the putative heterodimerization of the mu opioid receptor and the chemokine receptor CCR5.
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DOI：
10.1039/c2ob06801j
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发表时间：
2012-04-07
影响因子：
3.2
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Yuan Y;Arnatt CK;Li G;Haney KM;Ding D;Jacob JC;Selley DE;Zhang Y
二价配体方法不仅用于研究G蛋白偶联受体二聚化和/或寡聚化的潜在机制，而且旨在通过靶向该过程来增强配体亲和力和/或选择性，从而潜在地治疗多种疾病。药物滥用和成瘾使人类免疫缺陷病毒（HIV）感染的预防和治疗变得更加困难。广泛研究表明，吗啡是一种 mu 阿片受体 (MOR) 激动剂，可以通过上调趋化因子受体 CCR5（众所周知的 HIV 入侵宿主细胞的共受体）的表达来加速 HIV 感染。与此同时，两个研究小组在他们的独立研究中描述了假定的 MOR/CCR5 异二聚体。本文的目的是报告二价配体的设计和合成，以探索假定的 MOR/CCR5 二聚现象的生物学和药理学过程。因此，开发的二价配体包含通过间隔基连接的两个不同的药效团；理想情况下，其中一个与 MOR 相互作用，另一个与 CCR5 相互作用。选择纳曲酮和马拉维罗作为药效团来生成这样的二价探针。制备该二价配体的总体反应路线收敛且高效，涉及十六个步骤，产率中等至良好。初步生物学表征表明，二价化合物1保留了两个药效团分别对MOR和CCR5的药理特征，且结合亲和力相对较低，初步验证了我们最初的分子设计。
The bivalent ligand approach has been utilized not only to study the underlying mechanism of G protein-coupled receptors dimerization and/or oligomerization, but also aimed to enhance ligand affinity and/or selectivity for potential treatment of a variety of diseases by targeting this process. Substance abuse and addiction have made both the prevention and the treatment of human immunodeficiency virus (HIV) infection more difficult to tackle. It has been extensively studied that morphine, a mu opioid receptor (MOR) agonist, can accelerate HIV infection through up-regulating the expression of the chemokine receptor CCR5, a well-known co-receptor for HIV invasion to the host cells. Meanwhile, two research groups have described the putative MOR/CCR5 heterodimers in their independent studies. The purpose of this paper is to report the design and synthesis of a bivalent ligand to explore the biological and pharmacological process of the putative MOR/CCR5 dimerization phenomenon. The developed bivalent ligand thus contains two distinct pharmacophores linked through a spacer; ideally one of which will interact with the MOR and the other with the CCR5. Naltrexone and Maraviroc were selected as the pharmacophores to generate such a bivalent probe. The overall reaction route to prepare this bivalent ligand was convergent and efficient, and involved sixteen steps with moderate to good yields. The preliminary biological characterization showed that the bivalent compound 1 retained the pharmacological characteristics of both pharmacophores towards the MOR and the CCR5 respectively with relatively lower binding affinity, which tentatively validated our original molecular design.
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