雷莫必利的构象受限类似物作为潜在的抗精神病药物。

Conformationally restricted analogues of remoxipride as potential antipsychotic agents.

作者信息

Norman M H, Kelley J L, Hollingsworth E B

机构信息

Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.

出版信息

J Med Chem. 1993 Oct 29;36(22):3417-23. doi: 10.1021/jm00074a023.

DOI:10.1021/jm00074a023

PMID:7901417

Abstract

Several conformationally restricted derivatives of (S)-3-bromo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dimethoxybenzamide (remoxipride) were synthesized and evaluated in vitro for their ability to inhibit [3H]raclopride binding at the dopamine D-2 receptor. The cyclic benzamides designed to mimic the intramolecular hydrogen bonding of desmethylremoxipride (4, FLA-797) included 2,3-dihydro-4H-1,3-benzoxazin-4-ones, 2,3-dihydro-4H-1,3-benzthiazin-4-ones, phthalimides, 1-isoindolinones, 1,2-benzisothiazol-3(2H)-ones, and 1,2-benzisothiazol-3(2H)-one 1,1-dioxides. In this series, enhanced affinities to the dopamine D-2 receptor were not observed. The phthalimidine analogue 24b ((S)-6-chloro-2-(1-ethylpyrrolidinyl)-1-isoindolinone) exhibited the highest affinity to the dopamine D-2 receptor with an IC50 of 1.3 microM, which was equipotent to remoxipride.

摘要

合成了(S)-3-溴-N-((1-乙基-2-吡咯烷基)甲基)-2,6-二甲氧基苯甲酰胺（瑞莫必利）的几种构象受限衍生物，并在体外评估了它们抑制[3H]雷氯必利与多巴胺D-2受体结合的能力。设计用于模拟去甲基瑞莫必利（4，FLA-797）分子内氢键的环状苯甲酰胺包括2,3-二氢-4H-1,3-苯并恶嗪-4-酮、2,3-二氢-4H-1,3-苯并噻嗪-4-酮、邻苯二甲酰亚胺、1-异吲哚啉酮、1,2-苯并异噻唑-3(2H)-酮和1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物。在该系列中，未观察到对多巴胺D-2受体亲和力的增强。邻苯二甲酰亚胺类似物24b（(S)-6-氯-2-(1-乙基吡咯烷基)-1-异吲哚啉酮）对多巴胺D-2受体表现出最高亲和力，IC50为1.3微摩尔，与瑞莫必利等效。