An investigation into the structural determinants of cannabinoid receptor ligand efficacy
An investigation into the structural determinants of cannabinoid receptor ligand efficacy
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DOI：
10.1038/sj.bjp.0702469
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发表时间：
1999-04-01
影响因子：
7.3
通讯作者：
Abood, ME
中科院分区：
文献类型：
--
作者：
Griffin, G;Wray, EJ;Abood, ME
1在大鼠小脑膜中的GTP γ S结合试验中测试了Delta（8）-THC的许多侧链类似物。O-1125是一种饱和侧链化合物，其E-max为165.0%，EC_（50）为17.4 nM。2 O-1236、O-1237和O-1238是侧链中含有顺式碳-碳双键的三烯基衍生物，作为部分激动剂，E-max值为51.3-87.5%，EC 50值为4.4 - 29.7 nM。3 O-1125，O-1236，O-1237和O-1238对GTP γ S结合的作用被CBI受体拮抗剂SR 141716 A拮抗。获得的K-B值范围为0.11-0.21 mM，表明对CB 1受体的作用。（O-584、O-806、O-823、O-1176和O-1184），每个在侧链中含有碳-碳三键，不刺激GTP γ S结合，并被测试为潜在的大麻素受体拮抗剂。炔基化合物拮抗四种大麻素受体激动剂对GTP γ S结合的刺激作用。获得的K-B值均在纳摩尔范围内，激动剂之间或小脑结合亲和力之间没有差异。6总之，经典大麻素结构侧链的改变可能对CB 1受体的亲和力和功效产生很大影响。7此外，这项研究证实了GTP γ S结合试验评估配体功效的离散差异的能力，这些差异可能在使用替代功能性抗体时无法观察到。分析，从而提供了一个独特的工具，用于评估配体功效的分子机制。
1 A number of side-chain analogues of Delta(8)-THC were tested in GTP gamma S binding assay in rat cerebellar membranes. O-1125, a saturated side-chain compound stimulated GTP gamma S binding with an E-max of 165.0%, and an EC50 Of 17.4 nM.2 O-1236, O-1237 and O-1238, three-enyl derivatives containing a cis carbon-carbon double bond in the side-chain, stimulated GTP gamma S binding, acting as partial agonists with E-max values ranging from 51.3-87.5% and EC50 values between 4.4 and 29.7 nM.3 The stimulatory effects of O-1125, O-1236, O-1237 and O-1238 on GTP gamma S binding were antagonized by the CBI receptor antagonist SR 141716A. The K-B Values obtained ranged from 0.11-0.21 mM, suggesting an action at CB1 receptors.4 Five-ynyl derivatives (O-584, O-806, O-823, O-1176 and O-1184), each containing a carbon-carbon triple bond in the side-chain, did not stimulate GTP gamma S binding and were tested as potential cannabinoid receptor antagonists.5 Each -ynyl compound antagonized the stimulatory effects of four cannabinoid receptor agonists on GTP gamma S binding. The K-B values obtained, all found to be in the nanomolar range, did not differ between agonists or from cerebellar binding affinity.6 In conclusion, alterations of the side-chain of the classical cannabinoid structure may exert a large influence on affinity and efficacy at the CB1 receptor.7 Furthermore, this study confirms the ability of the GTP gamma S binding assay to assess discrete differences in ligand efficacies which potentially may not be observed using alternative functional assays, thus providing a unique tool for the assessment of the molecular mechanisms underlying ligand efficacies.