Gilligan P J, Cain G A, Christos T E, Cook L, Drummond S, Johnson A L, Kergaye A A, McElroy J F, Rohrbach K W, Schmidt W K
Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0353.
J Med Chem. 1992 Nov 13;35(23):4344-61. doi: 10.1021/jm00101a012.
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.
σ受体配体代表了一类新型的潜在抗精神病药物。本文介绍了新型二取代哌啶σ配体的构效关系，这些配体对多巴胺D2受体几乎没有或没有亲和力。相对于多巴胺D2或5-羟色胺5-HT2受体，对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相对于其他哌啶取代基的取向所支配。在一些用于评估潜在抗精神病药物的动物模型中，这些化合物中有几种具有良好的口服效力。N-环丙基甲基酮和醚（例如6i（DuP 734）、6q、18a和18n）具有最佳的体内效力。化合物6i（DuP 734）和6q即使在非常高的剂量下也不会在大鼠中引起僵住症。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，不会诱发锥体外系副作用或迟发性运动障碍。
