Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor.
Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor.
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DOI：
10.1021/jm1006676
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发表时间：
2010-10-14
影响因子：
7.3
通讯作者：
Thomas BF
中科院分区：
文献类型：
--
作者：
Zhang Y;Gilliam A;Maitra R;Damaj MI;Tajuba JM;Seltzman HH;Thomas BF
许多G蛋白偶联受体（包括CB 1受体）的二聚或寡聚化现在已被广泛接受，并可能对靶向这些受体复合物的药物开发产生重大影响。开发了一个由两个相同的CB 1拮抗剂药效团组成的二价配体库，这些药效团由不同长度的间隔区连接而成，这些药效团来自SR 141716。这些二价配体在CB 1和CB 2受体的亲和力使用放射性标记的结合试验测定。通过GTP-γ-S积累和细胞内钙动员测定其功能活性。结果表明，接头的性质和它的长度是这些配体在CB 1受体结合位点的最佳相互作用的关键因素。最后，选择的二价配体（5d和7 b）能够在啮齿动物甩尾测定中减弱大麻素激动剂CP 55，940的抗伤害感受作用。这些新的化合物作为探针，将使进一步评估CB 1受体二聚化和寡聚化，其功能意义，并可能证明有用的新的治疗方法的发展G蛋白偶联受体介导的疾病。
Dimerization or oligomerization of many G protein-coupled receptors, including the CB1 receptor, is now widely accepted and may have significant implications towards 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 in a rodent tail-flick assay. These novel compounds as probes will enable further evaluation of CB1 receptor dimerization and oligomerization, its functional significance, and may prove useful in the development of new therapeutic approaches to G protein-coupled receptor mediated disorders.
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影响因子：
7.3
作者：
Franco, R.;Casado, V.;Canela, Ei
通讯作者：
Canela, Ei
影响因子：
7.3
作者：
Narlawar, Rajeshwar;Lane, J. Robert;IJzerman, Adriaan P.
通讯作者：
IJzerman, Adriaan P.
影响因子：
4.4
作者：
Mathews, Jennifer L.;Fulton, Brian S.;Bidlack, Jean M.
通讯作者：
Bidlack, Jean M.
影响因子：
7.3
作者：
Decker, Michael;Fulton, Brian S.;Neumeyer, John L.
通讯作者：
Neumeyer, John L.
影响因子：
2.9
作者：
Howes, R;Barril, X;Drysdale, MJ
通讯作者：
Drysdale, MJ