Recent Developments in Sigma-2 Receptor Compounds for Pain

After years of enigmatic pharmacology, non-selective ligands, and uncertain clinical application, sigma receptors have emerged as interesting therapeutic drug discovery-development targets. Two subtypes of sigma receptors have now been cloned, sigma-1 receptor (S1R) and sigma-2 receptor (S2R), and there has been much complementary and converging information from advances in molecular biology, computer modeling, virtual screening, and in vitro and in vivo testing. One of several evolving areas of therapeutic potential is for the treatment of pain. In particular, there is accumulating recent evidence from preclinical models that the demonstrated positive effects of S2R compounds in these models suggest possible positive implications for clinical effectiveness against pains that have a neuropathic component. Such pain conditions have imperfect therapeutic options currently. The addition of new drugs to the now available armamentarium would represent a very significant advance for the large number of patients who suffer from these types of intractable pain. Further research is needed to identify and characterize compounds that have not only good in vitro activity but also the characteristics needed to enter clinical trials. Here, we summarize some of the recent reports of the analgesic activity of S2R compounds.

在多年神秘的药理学研究、非选择性配体以及不确定的临床应用之后，西格玛受体已成为有趣的治疗药物研发靶点。西格玛受体的两种亚型现已被克隆，即西格玛 - 1受体（S1R）和西格玛 - 2受体（S2R），并且从分子生物学、计算机建模、虚拟筛选以及体内外试验的进展中获得了大量互补和趋同的信息。几个具有治疗潜力的不断发展的领域之一是疼痛治疗。特别是，来自临床前模型的近期证据不断积累，这些模型中S2R化合物所显示的积极效果表明，其对于具有神经病理性成分的疼痛的临床疗效可能具有积极意义。目前对于此类疼痛状况的治疗选择并不理想。为大量遭受此类顽固性疼痛的患者增加新的药物将是一项非常重大的进步。需要进一步的研究来识别和表征不仅在体外具有良好活性，而且具备进入临床试验所需特性的化合物。在此，我们总结了一些关于S2R化合物镇痛活性的近期报道。