Thomas B F, Compton D R, Martin B R, Semus S F
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Mol Pharmacol. 1991 Nov;40(5):656-65.
The structure-activity relationship studies that have been reported for cannabinoids suggest that 1) the conformation of the C-ring at the C9 position, 2) the A-ring phenolic hydroxyl, and 3) the hydrophobic side chain are important determinants for the production of analgesia, as well as other cannabinoid effects. However, either these previous structure-activity studies described for cannabinoid compounds have not been quantitative in nature or the prediction of the activity of known and unknown compounds based on molecular structure has not been tested in a comprehensive manner. In this study we describe a three-dimensional molecular modeling program using comparative molecular field analysis to derive quantitative structure-activity relationships fitting pharmacological potencies and binding affinities of cannabinoids. The analysis has proven to accurately fit the pharmacological activity of cannabinoid analogs, with cross-validated r2 values of greater than 0.3 and final analysis r2 values of greater than 0.88. Additionally, this study has further characterized the steric and electrostatic properties that account for the variations in their potency. The results from this study indicate that steric repulsion behind the C-ring is associated with decreased predicted binding affinity and pharmacological potency. On the other hand, the steric bulk of a side chain that is extended up to seven carbons contributes to predictions of increased binding affinity and potency. The electrostatic fields of cannabinoid analogs also contribute to the predicted in vitro and in vivo potencies. If the biological activities we have investigated are assumed to be the result of interaction with a single binding site, this method indicates the structural and physicochemical properties necessary for binding to the receptor and producing an effect. By defining cannabinoid binding affinity and behavioral activity pharmacophores, this method can be used for designing cannabinoid agonists and it is capable of predicting the activity of unknowns, thereby serving to facilitate rational drug design.
1）C9位C环的构象；2）A环酚羟基；3）疏水侧链是产生镇痛作用以及其他大麻素效应的重要决定因素。然而，之前针对大麻素化合物所描述的这些构效研究本质上并非定量研究，或者基于分子结构对已知和未知化合物活性的预测尚未得到全面验证。在本研究中，我们描述了一个三维分子建模程序，该程序使用比较分子场分析来推导适合大麻素药理效力和结合亲和力的定量构效关系。分析已证明能准确拟合大麻素类似物的药理活性，交叉验证的r2值大于0.3，最终分析的r2值大于0.88。此外，本研究进一步表征了导致其效力变化的空间和静电性质。该研究结果表明，C环后方的空间排斥与预测的结合亲和力和药理效力降低有关。另一方面，延伸至七个碳的侧链的空间体积有助于预测结合亲和力和效力的增加。大麻素类似物的静电场也有助于预测体外和体内效力。如果我们所研究的生物活性被假定为与单一结合位点相互作用的结果，那么该方法表明了与受体结合并产生效应所需的结构和物理化学性质。通过定义大麻素结合亲和力和行为活性药效基团，该方法可用于设计大麻素激动剂，并且能够预测未知物的活性，从而有助于促进合理药物设计。
