QSAR analysis of Delta(8)-THC analogues: relationship of side-chain conformation to cannabinoid receptor affinity and pharmacological potency.
QSAR analysis of Delta(8)-THC analogues: relationship of side-chain conformation to cannabinoid receptor affinity and pharmacological potency.
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Delta(8)-THC 类似物的 QSAR 分析：侧链构象与大麻素受体亲和力和药理效力的关系。
DOI：
10.1021/jm9902281
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发表时间：
2000
影响因子：
7.3
通讯作者：
Thomas,BF
中科院分区：
文献类型：
--
作者：
Keimowitz,AR;Martin,BR;Razdan,RK;Crocker,PJ;Mascarella,SW;Thomas,BF
报道了一种新的Δ8-四氢大麻酚（Δ8-THC）类似物侧链结构的定量构效关系（QSAR）。使用计算分子建模和QSAR分析研究了一系列具有广泛药理学效力和CB 1受体亲和力的36个侧链取代的Δ8-THC。每个化合物的侧链的构象的流动性，其特征在于使用淬灭的分子动力学方法。定量构效关系技术包括改进的活性类似物方法（MAA），多元线性回归分析（MLR），和比较分子场分析（CoMFA）的研究。所有这三种方法都产生了一致的结果。MAA的方法应用到一组烯烃/炔烃对确定最活跃的构象与构象的流动性限制在一个大约8毫米半径。MLR分析（仅限于15种烃侧链类似物）确定了描述侧链长度和末端位置的两个变量，这两个变量能够拟合受体亲和力的药理学数据，pKD的相关系数为0.82。虽然发现链长与受体亲和力直接相关，但发现侧链从其连接点到其末端的角度（由C3-C1 '-侧链末端碳定义的角度，见图1）与亲和力呈负相关。这些结果表明，预计侧链长度的增加和侧链包裹环系统的能力的增加会增加亲和力。因此，侧链的构象移动性不能限制链直接远离环系统，但必须允许链向环系统折回。最后，CoMFA分析涉及所有36种类似物;他们还提供了支持以下假设的数据：为了获得最佳亲和力和效力，侧链必须具有构象自由度，允许其末端折叠并接近酚环。
A novel quantitative structure−activity relationship (QSAR) for the side-chain region of Δ8-tetrahydrocannabinol (Δ8-THC) analogues is reported. A series of 36 side-chain-substituted Δ8-THCs with a wide range of pharmacological potency and CB1 receptor affinity was investigated using computational molecular modeling and QSAR analyses. The conformational mobility of each compound's side chain was characterized using a quenched molecular dynamics approach. The QSAR techniques included a modified active analogue approach (MAA), multiple linear regression analyses (MLR), and comparative molecular field analysis (CoMFA) studies. All three approaches yielded consistent results. The MAA approach applied to a set of alkene/alkyne pairs identified the most active conformers as those with conformational mobility constrained within an approximately 8 Å radius. MLR analyses (restricted to 15 hydrocarbon side-chain analogues) identified two variables describing side-chain length and terminus position that were able to fit the pharmacological data for receptor affinity with a correlation coefficient for pKDof 0.82. While chain length was found to be directly related to receptor affinity, the angle made by the side chain from its attachment point to its terminus (angle defined by C3−C1‘−side-chain terminus carbon, see Figure 1) was found to be inversely related to affinity. These results suggest that increased side-chain length and increased side-chain ability to wrap around the ring system are predicted to increase affinity. Therefore, the side chain's conformational mobility must not restrict the chain straight away from the ring system but must allow the chain to wrap back around toward the ring system. Finally, the CoMFA analyses involved all 36 analogues; they also provided data to support the hypothesis that for optimum affinity and potency the side chain must have conformational freedom that allows its terminus to fold back and come into proximity with the phenolic ring.