Department of Biochemistry and Physiology. Faculty of Pharmacy and Food Sciences. Universitat de Barcelona, Barcelona 08028, Spain; Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona 08035, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid 28031, Spain.
Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
Pharmacol Res. 2024 Oct;208:107363. doi: 10.1016/j.phrs.2024.107363. Epub 2024 Aug 22.
G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB receptor (CBR) homodimerization by simultaneously binding both protomers of the CBR-CBR homodimer. Computational and pharmacological experiments showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This results in unique pharmacological properties, including increased potency in G-mediated signaling and enhanced recruitment of β-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CBR activity, potentially leading to improved therapeutic outcomes.
G 蛋白偶联受体（GPCRs）存在于可相互转换的构象状态景观中，并处于单体和更高阶寡聚体之间的动态平衡中，这两者均受配体结合的影响。在这里，我们表明，由相同的色烯并吡唑部分作为药效团形成的同双价配体，通过 14 个亚甲基单元连接，可通过同时结合 CBR-CBR 同源二聚体的两个前体来调节大麻素 CB 受体（CBR）同源二聚体的动力学。计算和药理学实验表明，配体药效团之一结合到一个前体的正位点，而另一个药效团结合到跨膜 1 和 7 之间的面向膜的口袋中伙伴前体。这导致了独特的药理学特性，包括在 G 介导的信号传导中增加效力和增强β-抑制蛋白的募集。因此，通过调节二聚体动力学，可能可以微调 CBR 的活性，从而有可能改善治疗效果。
