用于改善认知障碍的靶向α7型尼古丁乙酰胆碱受体正向变构调节剂的研发现状

Current Landscape for Research and Development of α7-Nicotine Acetylcholine Receptor Targeting Positive Allosteric Modulators for Improvement of Cognitive Impairment

随着全球人口老龄化加剧,阿尔茨海默病已成为威胁人类健康的重大疾病之一。目前尚无明显改善该病患者认知功能的药物,是未被满足的医疗需求和极具挑战的研发方向。研究表明,增强α7型尼古丁乙酰胆碱受体(n ACh R)功能可改善认知障碍和神经免疫功能。与激动剂的作用方式不同,α7正向变构调节剂(α7 PAMs)仅增强内源性乙酰胆碱递质激活n ACh R的功能,具有不易产生脱敏和潜在毒副作用较小的特点,是潜在治疗阿尔茨海默病的新策略。结合文献和笔者所在课题组的近期研究工作,重点介绍α7 nAChR及其正向变构调节剂(α7 nAChR PAMs)的结构与生物学评价,以期推动能改善认知功能障碍的α7 nAChR PAMs的研发进程。

With the aggravation of global problem of aging, Alzheimer’s disease has become one of the major threats of human health. At present, there are no effective drugs that can significantly improve cognitive function of patients with Alzheimer’s disease, which presents an unmet medical need and an extreme challenge. Studies have shown that enhancing α7-nicotine acetylcholine receptor(n ACh R) function can improve cognitive impairment and neuroimmunity. Distinct from agonists, α7 positive allosteric modulators(α7 PAMs) enhance the function of nAChR only in the presence of endogenous transmitter acetylcholine, and are also characterized by less desensitization and potential toxic and side effects. Therefore, targeting α7 by PAMs emerges as a new strategy for potential treatment of Alzheimer’s disease. This review focuses on recent literature and our research progress on the discovery of α7 nAChR PAMs and their biological evaluation, which is expected to promote the research and development of novel α7 nAChR PAMs for improvement of cognitive impairment common to neuropsychiatric disorders.