Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, USA.
Org Biomol Chem. 2012 Apr 7;10(13):2633-46. doi: 10.1039/c2ob06801j. Epub 2012 Feb 22.
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 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. 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 and this has been extensively studied. 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.
双配体方法不仅被用于研究 G 蛋白偶联受体二聚化和/或寡聚化的潜在机制，还被用于通过靶向该过程来增强配体的亲和力和/或选择性，以潜在治疗各种疾病。药物滥用和成瘾使预防和治疗人类免疫缺陷病毒 (HIV) 感染变得更加困难。吗啡是一种μ阿片受体 (MOR) 激动剂，通过上调趋化因子受体 CCR5 的表达，加速 HIV 感染，CCR5 是 HIV 入侵宿主细胞的公认辅助受体，这已被广泛研究。同时，两个研究小组在各自的研究中描述了假定的 MOR-CCR5 异源二聚体。本文的目的是报告一种双配体的设计和合成，以探索假定的 MOR-CCR5 二聚化现象的生物学和药理学过程。开发的双配体因此包含通过间隔基连接的两个不同的药效团；理想情况下，其中一个将与 MOR 相互作用，另一个与 CCR5 相互作用。纳曲酮和马拉维若被选为药效团来生成这样的双价探针。制备这种双配体的总反应路线是收敛的和有效的，涉及十六步，具有中等至良好的收率。初步的生物学特征表明，双价化合物 1 保留了两个药效团对 MOR 和 CCR5 的药理学特征，其结合亲和力相对较低，这初步验证了我们最初的分子设计。
