Mottola D M, Laiter S, Watts V J, Tropsha A, Wyrick S D, Nichols D E, Mailman R B
Brain and Development Research Center, School of Medicine, University of North Carolina, Chapel Hill, USA.
J Med Chem. 1996 Jan 5;39(1):285-96. doi: 10.1021/jm9502100.
Compute-aided conformational analysis was used to characterize the agonist pharmacophore for D1 dopamine receptor recognition and activation. Dihydrexidine (DHX), a high-affinity full agonist with limited conformational flexibility, served as a structural template that aided in determining a molecular geometry that would be common for other more flexible, biologically active agonists. The intrinsic activity of the drugs at D1 receptors was assessed by their ability to stimulate adenylate cyclase activity in rat striatal homogenates (the accepted measure of D1 receptor activation). In addition, affinity data on 12 agonists including six purported full agonists (dopamine, dihydrexidine, SKF89626, SKF82958, A70108, and A77636), as well as six less efficacious structural analogs, were obtained from D1 dopamine radioreceptor-binding assays. The active analog approach to pharmacophore building was applied as implemented in the SYBYL software package. Conformational analysis and molecular mechanics calculations were used to determine the lowest energy conformation of the active analogs (i.e., full agonists), as well as the conformations of each compound that displayed a common pharmacophoric geometry. It is hypothesized that DHX and other full agonists may share a D1 pharmacophore made up of two hydroxy groups, the nitrogen atom (ca. 7 A from the oxygen of m-hydroxyl) and the accessory ring system characterized by the angle between its plane and that of the catechol ring (except for dopamine and A77636). For all full agonists (DHX, SKF89626, SKF82958, A70108, A77636, and dopamine), the energy difference between the lowest energy conformer and those that displayed a common pharmacophore geometry was relatively small (< 5 kcal/mol). The pharmacophoric conformations of the full agonists were also used to infer the shape of the receptor binding site. Based on the union of the van der Waals density maps of the active analogs, the excluded receptor volume was calculated. Various inactive analogs (partial agonists with D1 K0.5 > 300 nM) subsequently were used to define the receptor essential volume (i.e., sterically intolerable receptor regions). These volumes, together with the pharmacophore results, were integrated into a three-dimensional model estimating the D1 receptor active site topography.
计算机辅助构象分析用于表征D1多巴胺受体识别和激活的激动剂药效基团。二氢麦角隐亭（DHX）是一种构象灵活性有限的高亲和力完全激动剂，作为一种结构模板，有助于确定其他更具灵活性的生物活性激动剂共有的分子几何结构。通过药物刺激大鼠纹状体匀浆中腺苷酸环化酶活性的能力（这是公认的D1受体激活指标）来评估药物在D1受体上的内在活性。此外，通过D1多巴胺放射受体结合试验获得了12种激动剂的亲和力数据，其中包括6种所谓的完全激动剂（多巴胺、二氢麦角隐亭、SKF89626、SKF82958、A70108和A77636）以及6种效力较低的结构类似物。药效基团构建采用活性类似物方法，如SYBYL软件包中所实现的那样。构象分析和分子力学计算用于确定活性类似物（即完全激动剂）的最低能量构象，以及显示出共同药效基团几何结构的每种化合物的构象。据推测，DHX和其他完全激动剂可能共享一个由两个羟基、氮原子（距间位羟基的氧约7埃）以及由其平面与儿茶酚环平面之间的角度所表征的辅助环系统组成的D1药效基团（多巴胺和A77636除外）。对于所有完全激动剂（DHX、SKF89626、SKF82958、A70108、A77636和多巴胺），最低能量构象与显示出共同药效基团几何结构的构象之间的能量差相对较小（<5千卡/摩尔）。完全激动剂的药效基团构象也用于推断受体结合位点的形状。基于活性类似物的范德华密度图的并集，计算出排除的受体体积。随后使用各种无活性类似物（D1 K0.5>300 nM的部分激动剂）来定义受体必需体积（即空间上不可容忍的受体区域）。这些体积与药效基团结果一起被整合到一个估计D1受体活性位点拓扑结构的三维模型中。
