New J S, Yevich J P, Eison M S, Taylor D P, Eison A S, Riblet L A, VanderMaelen C P, Temple D L
J Med Chem. 1986 Aug;29(8):1476-82. doi: 10.1021/jm00158a026.
Several analogues of the novel anxiolytic buspirone were synthesized and evaluated in vivo for tranquilizing activity and their ability to reverse neuroleptic-induced catalepsy. The in vitro binding affinities of these compounds were also examined for both the alpha 1 and dopamine D2 receptor systems. The general structure-activity relationships of this series highlight compounds 17, 21, and 32 as having anticonflict activity. Each of these structures contains the 1-(2-pyrimidinyl)piperazine moiety linked by a tetramethylene chain to a variable cyclic imide moiety. Compound 32 (4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6- piperidinedione) was found to be equipotent with buspirone in its anxiolytic activity and was therefore selected for extensive preclinical characterization. The pharmacology of buspirone and 32 is contrasted, and the potent serotonin agonist properties of 32 are discussed with reference to its potential contribution to the anxioselective mechanism of this compound.
合成了新型抗焦虑药丁螺环酮的几种类似物，并在体内对其镇静活性及逆转抗精神病药物所致僵住症的能力进行了评估。还研究了这些化合物对α1和多巴胺D2受体系统的体外结合亲和力。该系列化合物的一般构效关系表明，化合物17、21和32具有抗冲突活性。这些结构中的每一个都包含通过四亚甲基链与可变环状酰亚胺部分相连的1-(2-嘧啶基)哌嗪部分。发现化合物32（4,4-二甲基-1-[4-[4-(2-嘧啶基)-1-哌嗪基]丁基]-2,6-哌啶二酮）在抗焦虑活性方面与丁螺环酮相当，因此被选用于广泛的临床前特性研究。对比了丁螺环酮和32的药理学，并参照32对该化合物抗焦虑选择性机制的潜在贡献讨论了其强效血清素激动剂特性。
