NOVEL PIPERIDINE SIGMA RECEPTOR LIGANDS AS POTENTIAL ANTIPSYCHOTIC-DRUGS
NOVEL PIPERIDINE SIGMA RECEPTOR LIGANDS AS POTENTIAL ANTIPSYCHOTIC-DRUGS
复制标题
DOI：
10.1021/jm00101a012
复制
发表时间：
1992-11-13
影响因子：
7.3
通讯作者：
TAM, SW
中科院分区：
文献类型：
--
作者：
GILLIGAN, PJ;CAIN, GA;TAM, SW
σ受体配体代表了一类新的潜在抗精神病药物。本文介绍了导致新的二取代哌啶σ配体，多巴胺D2受体的亲和力很小或没有的构效关系。对多巴胺D2或5-羟色胺5-HT 2受体的σ位点的选择性似乎受哌啶氮取代基的化学性质、其与碱性氮的距离以及其相对于其他哌啶取代基的取向所支配。这些化合物中的几种在用于评估潜在抗精神病药物的一些动物模型中具有良好的口服效力。N-环丙基甲基酮和醚（例如6 i（DuP 734）、6 q、18 a和18 n）具有最佳的体内效力。化合物6 i（DuP 734）和6 q即使在非常高的剂量下也不引起大鼠的僵住症。基于这些σ配体的药理学特征，我们提出这些化合物可能是有效的抗精神病药物，其不诱导锥体外系副作用或迟发性运动障碍。
Sigma receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine sigma ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for sigma sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these sigma ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.