Högberg T, Norinder U, Rämsby S, Stensland B
Research and Development Laboratories, Astra Alab AB, Södertälje, Sweden.
J Pharm Pharmacol. 1987 Oct;39(10):787-96. doi: 10.1111/j.2042-7158.1987.tb05120.x.
The structure of the potent dopamine-D2 antagonist, raclopride, (S)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamid e (+)-tartrate, has been determined by X-ray crystallography. The benzamide moiety of raclopride is planar in accordance with other salicylamides (FLA 797 and eticlopride). The planar conformation is stabilized by two intramolecular hydrogen bonds, i.e. one between the amide hydrogen and the methoxy group and one between the phenol hydrogen and the carbonyl group. The side-chain of raclopride has an extended conformation in contrast to the solid state conformations of FLA 797 and eticlopride. The side-chain conformations were studied by rigid rotations followed by MM2PI relaxations of the eight local minima found. Small energy differences (less than 4.0 kcal mol-1) exist between the various extended and folded conformations. Based on modelling studies with piquindone as template, it is suggested that the salicylamides with N-ethyl-2-pyrrolidinylmethyl side-chains interact with the dopamine-D2 receptor in a folded or a half-folded conformation.
强效多巴胺 D2 拮抗剂雷氯必利（(S)-3,5-二氯-N-[(1-乙基-2-吡咯烷基)甲基]-6-甲氧基水杨酰胺 (+)-酒石酸盐）的结构已通过 X 射线晶体学确定。雷氯必利的苯甲酰胺部分与其他水杨酰胺（FLA 797 和依托必利）一样呈平面结构。该平面构象通过两个分子内氢键得以稳定，即酰胺氢与甲氧基之间的一个氢键以及酚氢与羰基之间的一个氢键。与 FLA 797 和依托必利的固态构象相比，雷氯必利的侧链具有伸展构象。通过刚性旋转以及对找到的八个局部极小值进行 MM2PI 松弛来研究侧链构象。各种伸展和折叠构象之间存在较小的能量差异（小于 4.0 kcal mol-1）。基于以匹喹酮为模板的建模研究，表明具有 N-乙基-2-吡咯烷基甲基侧链的水杨酰胺以折叠或半折叠构象与多巴胺 D2 受体相互作用。
