Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands.
Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands.
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发表时间：
1996-09
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通讯作者：
V. Showalter;D. R. Compton;Billy R. Martin;M. Abood
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作者：
V. Showalter;D. R. Compton;Billy R. Martin;M. Abood
迄今为止，已经确定了两种大麻素受体;一种主要位于中枢神经系统（CB 1），而另一种仅位于外周（CB 2）。本研究的目的是进一步探索CB 2受体的结合要求，并寻找对任一大麻素受体表现出不同亲和力的化合物。使用过滤测定法在克隆的人CB 1和CB 2受体上测定了先前在CB 1受体上测试的一系列大麻素的结合亲和力。此外，检查了CB 2受体的可能变构调节。钠和GTP类似物引起与CB 2受体特异性结合的浓度依赖性降低。大麻酚对CB 2受体的亲和力（Ki = 96.3 +/- 14 nM）被证实与δ 9-THC的亲和力（Ki = 36.4 +/- 10 nM）在大致相同的范围内。在克隆的CB 1和CB 2受体的亲和力进行了比较，在大脑中确定的亲和力。虽然大多数选择的化合物没有区分CB 1和CB 2，几个配体被确定为显示出选择性。亲和力比表明，大麻素的两个2 '-氟类似物对CB 1受体的选择性超过23倍，并证实了SR 141716 A {N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺盐酸盐}的CB 1选择性。此外，WIN-55，212-2 {（R）-（+）-[2，3-二氢-5-甲基-3-[（4-吗啉基）甲基]吡咯并[1，2，3-de]-1，4-苯并恶嗪-6-基]（1-萘基）甲酮}和密切相关的丙基吲哚类似物显示对CB 2受体的选择性分别为6.75和27.5倍。这些配体现在可以作为设计具有更高选择性的化合物的基础。
Two cannabinoid receptors have been identified to date; one is located predominantly in the central nervous system (CB1), whereas the other is located exclusively in the periphery (CB2). The purposes of this study were to explore further the binding requirements of the CB2 receptor and to search for compounds displaying distinct affinities for either cannabinoid receptor. The binding affinities of a series of cannabinoids tested previously at the CB1 receptor were determined at cloned human CB1 and CB2 receptors using a filtration assay. In addition, possible allosteric regulation of the CB2 receptor was examined. Sodium and a GTP analog elicited a concentration-dependent decrease in specific binding to the CB2 receptor. The affinity of cannabinol for CB2 receptors (Ki = 96.3 +/- 14 nM) was confirmed to be in approximately the same range as that of delta 9-THC (Ki = 36.4 +/- 10 nM). Affinities at cloned CB1 and CB2 receptors were compared with affinities determined in the brain. Although most of the chosen compounds did not discriminate between CB1 and CB2, several ligands were identified that showed selectivity. Affinity ratios demonstrated that two 2'-fluoro analogs of anandamide were over 23-fold selective for the CB1 receptor and confirmed the CB1 selectivity of SR141716A {N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamidehydrochloride}. In addition, WIN-55, 212-2 {(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl) methyl] pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl) methanone} and a closely related propyl indole analog were shown to be 6.75- and 27.5- fold selective, respectively, for the CB2 receptor. These ligands can now serve as a basis for the design of compounds with even greater selectivity.