King F D, Hadley M S, McClelland C M
Beecham Pharmaceuticals Research Division, Medicinal Research Centre, Harlow, Essex, England.
J Med Chem. 1988 Sep;31(9):1708-12. doi: 10.1021/jm00117a008.
The substituted benzamides metoclopramide (1) and clebopride (3) are stimulants of gastric motility. They are also central dopamine receptor antagonists with 3 being the more potent. This is presumed to be due to an additional interaction of its N-benzyl group with the receptor. The effect of restricting the conformation of this group by replacing the N-benzylpiperidine side chain of 3 by phenyl-substituted quinolizidines and indolizidines has been investigated. Only the indolizidines had significant activity, the nature of which depended upon the orientation of the phenyl substituent. The 2 alpha-phenyl isomers 5d-h were potent central dopamine D2 receptor antagonists with 5h showing selectivity for the limbic system. The 2 beta-phenyl isomer 5c was a gastric motility stimulant devoid of significant central dopamine receptor antagonist activity. Implications on receptor models are discussed.
取代苯甲酰胺类药物甲氧氯普胺（1）和氯波必利（3）是胃动力刺激剂。它们也是中枢多巴胺受体拮抗剂，其中3的活性更强。据推测，这是由于其N-苄基与受体的额外相互作用。通过用苯基取代的喹嗪和中氮茚取代3的N-苄基哌啶侧链来限制该基团构象的影响已被研究。只有中氮茚具有显著活性，其性质取决于苯基取代基的取向。2α-苯基异构体5d-h是强效的中枢多巴胺D2受体拮抗剂，其中5h对边缘系统具有选择性。2β-苯基异构体5c是一种胃动力刺激剂，没有显著的中枢多巴胺受体拮抗剂活性。文中讨论了对受体模型的影响。
