Martin G E, Elgin R J, Mathiasen J R, Davis C B, Kesslick J M, Baldy W J, Shank R P, DiStefano D L, Fedde C L, Scott M K
Department of Biological Research, McNeil Pharmaceutical and Janssen Research Foundation Worldwide, Spring House, Pennsylvania 19477.
J Med Chem. 1989 May;32(5):1052-6. doi: 10.1021/jm00125a020.
Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
一般来说，抗精神病药物是多巴胺受体阻断剂，同时也能阻断大鼠的条件性回避反应（CAR）。然而，最近有报道称，（对甲氧基苯基）哌嗪（OMPP，1h）和（间氯苯基）哌嗪（MCPP，1o）虽然都不具有多巴胺受体阻断特性，但却能阻断大鼠的条件性回避反应。本文研究了多种其他取代苯基哌嗪的行为和生化特征。所测试的苯基哌嗪中，没有一种对多巴胺D-1或D-2受体位点具有高亲和力，但许多都能有效阻断CAR。结果表明，苯基哌嗪可能是不阻断多巴胺受体的有效抗精神病药物。此外，活性化合物在置换与血清素受体结合的配体方面确实表现出活性。测定了5-HT-1A和5-HT-1B结合位点以及5-HT-2位点的受体结合特征。这项临床前试验的数据表明，这些苯基哌嗪可能是通过非多巴胺能作用机制发挥作用的有效抗精神病药物。
