Pettersson I, Liljefors T, Bøgesø K
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
J Med Chem. 1990 Aug;33(8):2197-204. doi: 10.1021/jm00170a025.
Comprehensive conformational analysis using molecular mechanics calculations (MM2(85)) has been carried out for the potent and selective dopamine D-1 receptor agonist 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1; SK&F 38393), the antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (8; SCH 23390), and several analogues, including conformationally constrained ones. Calculated conformational energies have been related to pharmacological and biochemical data in an attempt to identify the biologically active conformations of 1 and 8. It is concluded that the most probable receptor-bound conformation in both cases is a chair conformation with an equatorial phenyl ring and for 8 an equatorial N-methyl group. It is suggested that the orientation of the phenyl ring in the receptor-bound molecule does not deviate in terms of dihedral angles by more than about 30 degrees from the preferred phenyl group rotamer in which the planes of two aromatic rings are essentially orthogonal.
已使用分子力学计算（MM2(85)）对强效选择性多巴胺D-1受体激动剂7,8-二羟基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓（1；SK&F 38393）、拮抗剂7-氯-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓（8；SCH 23390）以及包括构象受限类似物在内的几种类似物进行了全面的构象分析。计算得到的构象能量已与药理学和生化数据相关联，以试图确定1和8的生物活性构象。得出的结论是，在这两种情况下，最可能的受体结合构象是一种椅式构象，其中苯环位于赤道平面，对于8而言，N-甲基也位于赤道平面。有人提出，受体结合分子中苯环的取向在二面角方面与两个芳香环平面基本正交的优选苯基团旋转异构体的偏差不超过约30度。
