Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 2010 Oct 14;53(19):7048-60. doi: 10.1021/jm1006676.
Dimerization or oligomerization of many G-protein-coupled receptors (GPCRs), including the cannabinoid 1 (CB1) receptor, is now widely accepted and may have significant implications for medications development targeting these receptor complexes. A library of bivalent ligands composed of two identical CB1 antagonist pharmacophores derived from SR141716 linked by spacers of various lengths were developed. The affinities of these bivalent ligands at CB1 and CB2 receptors were determined using radiolabeled binding assays. Their functional activities were measured using GTP-γ-S accumulation and intracellular calcium mobilization assays. The results suggest that the nature of the linker and its length are crucial factors for optimum interactions of these ligands at CB1 receptor binding sites. Finally, selected bivalent ligands (5d and 7b) were able to attenuate the antinociceptive effects of the cannabinoid agonist CP55,940 (21) in a rodent tail-flick assay. These novel compounds may serve as probes that will enable further characterization of CB1 receptor dimerization and oligomerization and its functional significance and may prove useful in the development of new therapeutic approaches to G-protein-coupled receptor mediated disorders.
许多 G 蛋白偶联受体（GPCR）的二聚化或寡聚化，包括大麻素 1（CB1）受体，现在已经被广泛接受，这可能对针对这些受体复合物的药物开发产生重大影响。我们开发了一个由两个相同的 CB1 拮抗剂药效团组成的二价配体库，这些药效团通过不同长度的间隔基连接。使用放射性标记的结合测定法测定这些二价配体在 CB1 和 CB2 受体上的亲和力。使用 GTP-γ-S 积累和细胞内钙动员测定法测量它们的功能活性。结果表明，接头的性质及其长度是这些配体在 CB1 受体结合部位最佳相互作用的关键因素。最后，选定的二价配体（5d 和 7b）能够在啮齿动物尾巴闪烁试验中减弱大麻素激动剂 CP55940（21）的镇痛作用。这些新型化合物可用作探针，进一步表征 CB1 受体二聚化和寡聚化及其功能意义，并可能有助于开发治疗 G 蛋白偶联受体介导疾病的新方法。
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