Sigma-1受体是一类重要的跨膜蛋白，与多种中枢神经系统疾病的发生发展密切相关。基于目前靶向sigma-1受体药物研究现状及别构调节剂的独特优势，发展sigma-1受体别构调节剂已成为这一领域药物研发的必然趋势。近年来我们团队发现了一类新型sigma-1受体别构调节剂作为潜在抗癫痫药，即以SKF83959和SOMCL-668为代表的1-芳基苯氮卓衍生物。然而，1－芳基苯氮卓曾是多巴胺D1受体配体的经典骨架，存在生物利用度低、代谢稳定性差及内在活性低等缺点。本项目拟在我们前期建立的靶向多巴胺D1受体苯氮卓衍生物构效关系的基础上，利用假设的sigma-1受体别构调节剂的药效团模型，发展一批全新的苯氮卓类选择性sigma-1受体别构调节剂，进一步完善其构效关系，同时采用前药理念和非经典生物电子等排原理改善化合物的成药性，以期得到1－2个有开发前景的候选化合物。

The human sigma-1 receptor is a vital transmembrane protein implicated in a variety of central nerve system diseases. Based on current status of drugs targeting sigma-1 receptors and unique advantages of allosteric modulators, development of sigma-1 allosteric modulators will be inevitable trend. We recently have found 1-aryl-N3-benzazepines, such as SKF83959 and SOMCL-668, are novel allosteric modulators of sigma-1 receptors as potential antiepileptic drugs. Unfortunately, most of 1-aryl-N3-benzazepines, ever as classic scaffolds of dopamine D1 ligands, has the shortcomings of poor bioavailability, low metabolic stability, and limited in vivo efficacy. Based on our previous SAR studies of benzazepines targeting D1 receptors and presumed sigma-1 pharmacophore model, we will develop a batch of novel benzazepines as selective sigma-1 allosteric modulators to further establish SAR studies, as well as employ the prodrug concept and the atypical bioisosterism to improve their druglike properties, leading to develop 1-2 promising candidates.