Reitz A B, Baxter E W, Bennett D J, Codd E E, Jordan A D, Malloy E A, Maryanoff B E, McDonnell M E, Ortegon M E, Renzi M J
R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA.
J Med Chem. 1995 Oct 13;38(21):4211-22. doi: 10.1021/jm00021a010.
N1-(2-Alkoxyphenyl)piperazines additionally containing an N4-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) test predictive of clinical antipsychotic activity and in in vitro receptor-binding assays. Certain of the compounds display high affinity for the D2, 5-HT1A, and alpha 1-adrenergic receptors. Structures bearing acyclic amide, lactam, and imide functionalities display good biological activity, with a preference for the 1,3-disubstituted phenyl ring relative to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible position of hydantoin attachment was investigated (e.g., substitution at N1, N3, and C5). The hydantoin involving attachment to N1 (24) was found to have good biological activity, whereas those hydantoins with attachment to N3 or C5 (22, 23, and 25) were inactive. Several of the smaller acetylated derivatives (30 and 33) have fair in vivo activity, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the D2 receptor (65 nM) as well as excellent in vivo activity. Benzylamino compounds display (viz. 27 and 35-38) moderate CAR activity but have surprising receptor affinity, often greater than those of comparable structures bearing a carbonyl (36 vs 7). Benzyl and benzhydryl alcohol compounds 40-48 are more active than amino structures 27 and 35-38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and 5-HT1A receptor binding.
制备了另外含有带有醇、酰胺、酰亚胺或乙内酰脲官能团的N4-苄基的N1-(2-烷氧基苯基)哌嗪，并在预测临床抗精神病活性的条件性回避反应（CAR）试验和体外受体结合试验中进行了评估。某些化合物对D2、5-HT1A和α1-肾上腺素能受体显示出高亲和力。带有无环酰胺、内酰胺和酰亚胺官能团的结构显示出良好的生物活性，相对于1,4-和1,2-同系物（7对10和12），更倾向于1,3-二取代苯环。研究了乙内酰脲连接的每个可能位置（例如，在N1、N3和C5处的取代）。发现连接到N1的乙内酰脲（24）具有良好的生物活性，而连接到N3或C5的那些乙内酰脲（22、23和25）没有活性。几种较小的乙酰化衍生物（30和33）具有相当的体内活性，而较大的苯甲酰类似物31则没有这种活性。尿嘧啶同系物34对D2受体具有适度的亲和力（65 nM）以及出色的体内活性。苄基氨基化合物（即27和35-38）显示出中等的CAR活性，但具有令人惊讶的受体亲和力，通常大于带有羰基的类似结构（36对7）。苄醇和二苯甲醇化合物40-48比氨基结构27和35-38更具活性，并且在CAR试验中也表现出出色的体内活性，同时具有适度的D2和5-HT1A受体结合。
