σ受体是与神经系统疾病和癌症病理学相关的一种独特类型的受体，其中一个亚型σ1 受体作为治疗神经系统疾病和可卡因成瘾的新靶点脱颖而出。我们前期工作中，通过巧妙的利用σ1 受体配体和尼古丁受体配体药效团之间的关系，鉴定了一类新型的异噁唑类σ1 受体配体化合物。其中化合物15对σ1 受体的亲和性达到4.2 nM，对σ2受体的亲和性为1312 nM，在美国NIH PDSP筛选平台中，15对常见的神经系统相关的神经递质受体和转移体显示了很好的选择性。本项目拟对此工作进行进一步研究，探讨这种新型的异噁唑系列σ1 受体配体的构效关系及在神经系统疾病尤其是抑郁症或疼痛领域的潜在应用。根据σ1 受体配体药效团特征拟设计合成A，B，C，D四个化合物库，进行药理学测试，对活性较好化合物进行初步的ADME-Tox测试，所得优选化合物在动物行为学模型上进一步评价，力争得到新型的具有抗抑郁样作用的σ1受体配体先导物。

σ receptors were identified as an unique class of receptors implicated in the pathophysiology of various neurological disorders and cancer. σ1 receptors emerge as targets for the treatment of neurophychiatric diseases, cocaine addiction, and pain. We previously reported the identification of compound 15 as a selective σ1 ligand resulting from a comparative analysis of the pharmacophoric elements required for σ1 and nicotinic ligands. Compound 15 displayed high selectivity for the σ1 receptor (Ki, σ1 = 4.1 nM, Ki, σ2 = 1312 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. We propose to extend these studies to explore the SAR of this novel isoxazole series of σ1 receptor ligands and their potential use in nervous system diseases and disorders, depression and pain in particular. We shall design and synthesis four new series (A, B, C, D) of σ1 receptor ligands based on the pharmacophore requirements, accompanied by the evaluation of their pharmacology in binding and functional assays, and the assessment of preliminary ADME-Tox properties for the selected effective compounds for advanced screening in mouse models of depression, pain or SmartCube. Our innovative approach aim to development of novel small molecule σ1 receptor ligands with potential to move into clinical trials as antidepressants or antinociceptive medications.