Gilligan P J, Kergaye A A, Lewis B M, McElroy J F
DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0353.
J Med Chem. 1994 Feb 4;37(3):364-70. doi: 10.1021/jm00029a008.
Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whether restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses and the structure-activity relationships of these compounds are reported herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po).
基于西格玛受体配体在动物行为模型中的活性特征及其对多巴胺能功能的间接调节作用，它们已被认为是潜在的抗精神病药物。化合物15（DuP 734）是西格玛-1和5-羟色胺5HT2受体的联合拮抗剂，作为一种潜在的抗精神病药物已进入I期临床试验。制备了四氢萘1和2，以确定限制化合物15及其类似物的构象是否会导致结合选择性或体内特征的差异。本文报道了这些化合物的合成及其构效关系。一种还原衍生物14对西格玛-1和5-羟色胺5HT2受体具有高亲和力，并且在一些动物抗精神病模型中具有优异的口服活性。此外，化合物14在大鼠中高达90 mg/kg（口服）时不会引起僵住症。
