Norman M H, Minick D J, Rigdon G C
Division of Chemistry, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1996 Jan 5;39(1):149-57. doi: 10.1021/jm9502201.
A series of phthalimide and isoindolinone derivatives bridged to 4-(1,2-benzisothiazol-3-yl)-1-piperazinyl was prepared. The compounds were evaluated in vitro at dopamine D2 and serotonin 5-HT1a and 5-HT2 receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. The effects of bridge length and conformation on the biological activity of these potential antipsychotic agents are discussed. A four-carbon spacer provided optimal activity within the two homologous series. Conformational investigations of the lead compound, isoindolinone 2, were conducted in an attempt to account for the superior activity observed for the butyl derivatives. On the basis of NMR and molecular modeling studies, two types of folded structures were proposed and several conformationally restrained analogues were synthesized. In general, restrictions incorporated within the linking bridge were detrimental to activity.
制备了一系列与4-(1,2-苯并异噻唑-3-基)-1-哌嗪基相连的邻苯二甲酰亚胺和异吲哚啉酮衍生物。这些化合物在体外针对多巴胺D2、血清素5-HT1a和5-HT2受体进行了评估，并在体内测试了其拮抗阿扑吗啡诱导的小鼠攀爬反应的能力。讨论了桥长度和构象对这些潜在抗精神病药物生物活性的影响。一个四碳间隔基在两个同系物系列中提供了最佳活性。对先导化合物异吲哚啉酮2进行了构象研究，试图解释丁基衍生物所观察到的优异活性。基于核磁共振和分子模拟研究，提出了两种折叠结构类型，并合成了几种构象受限类似物。一般来说，连接桥中引入的限制对活性不利。
