Gordon R K, Breuer E, Padilla F N, Smejkal R M, Chiang P K
Department of Applied Biochemistry, Walter Reed Army Institute of Research, Washington, D. C. 20307-5100.
Mol Pharmacol. 1989 Nov;36(5):766-72.
Quantitative structure-activity relationships between pharmacological activities and physical properties of a series of 2,2-diphenylpropionate compounds were used to define the topography of the antagonist binding site of muscarinic receptors. XICAMM, a computer molecular modeling program, was used to calculate geometrical and topological values of the compounds. The compounds were tested for their antimuscarinic activities by: (a) inhibition of [N-methyl-3H]scopolamine binding to the muscarinic receptors of N4TG1 neuroblastoma cells, (b) inhibition of carbachol-induced alpha-amylase release from rat pancreas acini, and (c) blocking of acetylcholine-induced contraction of guinea pig ileum. To evaluate as clearly as possible only the effect of the bond distance on the potency of the synthesized antimuscarinics, the compounds contained as many constant features as possible. Neither the hydrophobic nor the ester moieties of the compounds were changed, and the rings containing the protonated nitrogen were saturated and restricted. The antimuscarinic activities obtained from the three assays were significantly correlated with each other, with the exception of two compounds, 9 and 13. The latter two compounds demonstrated specificity for the m3 muscarinic receptor subtype expressed in the pancreas. Furthermore, it was demonstrated that the antimuscarinic activities were significantly related to the bond distances between the carbonyl oxygen (constant electronegative locus) and the protonated nitrogen (center of cationic charge) of the 2,2-diphenylpropionate compounds. Parabolic relationships between the pharmacological activities and bond distances were empirically established. The shortest calculated bond distance of these compounds was approximately 4.4 A, whereas the longest was about 5.9 A. The maximum antimuscarinic potency was observed with a calculated bond distance of about 5.2 A in all three assays.
利用一系列2,2 - 二苯基丙酸酯化合物的药理活性与物理性质之间的定量构效关系来确定毒蕈碱受体拮抗剂结合位点的拓扑结构。使用计算机分子建模程序XICAMM来计算这些化合物的几何和拓扑值。通过以下方式测试这些化合物的抗毒蕈碱活性：(a) 抑制 [N - 甲基 - 3H]东莨菪碱与N4TG1神经母细胞瘤细胞毒蕈碱受体的结合；(b) 抑制卡巴胆碱诱导的大鼠胰腺腺泡α - 淀粉酶释放；(c) 阻断乙酰胆碱诱导的豚鼠回肠收缩。为了尽可能清晰地评估键距对合成抗毒蕈碱剂效力的影响，这些化合物具有尽可能多的恒定特征。化合物的疏水部分和酯部分均未改变，且含有质子化氮的环是饱和且受限的。除了两种化合物（9号和13号）外，从这三种测定中获得的抗毒蕈碱活性彼此显著相关。后两种化合物对胰腺中表达的m3毒蕈碱受体亚型具有特异性。此外，还证明了抗毒蕈碱活性与2,2 - 二苯基丙酸酯化合物的羰基氧（恒定电负性位点）和质子化氮（阳离子电荷中心）之间的键距显著相关。通过实验建立了药理活性与键距之间的抛物线关系。这些化合物计算得到的最短键距约为4.4 Å，而最长键距约为5.9 Å。在所有三种测定中，计算得到的键距约为5.2 Å时观察到最大抗毒蕈碱效力。
