Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center , Omaha, NE, USA.
Expert Opin Investig Drugs. 2020 Jun;29(6):603-610. doi: 10.1080/13543784.2020.1764938. Epub 2020 May 12.
Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) partial agonists, agonists, and positive allosteric modulators (PAMs) have been in development for over a decade. The initial candidates were in clinical trials for a wide variety of diseases including schizophrenia, but there has yet to be a successful compound to make it to the market for any disorder. Although difficult to assess the cause of all the clinical failures, the lack of efficacy played a major role. The development of more selective compounds, may bring a successful compound to long-suffering schizophrenia patients.
This article examines investigational agonists and positive allosteric modulators of the α7 nicotinic receptor in preclinical studies as well as clinical trials. Our search included the use of SciFinder, Google, and clinicaltrials.gov with search dates of 2015 to the present.
Researchers must rethink their approach should look more closely at the selectivity of new compounds and how to tackle the translational gap. Perhaps new positive allosteric modulators that can help minimize receptor desensitization and selectivity profiles can be a path forward for α7 nAChRs in schizophrenia.
α7 烟碱型乙酰胆碱受体 (α7 nAChR) 部分激动剂、激动剂和正变构调节剂 (PAMs) 的开发已经超过十年。最初的候选药物已经在临床试验中用于治疗多种疾病，包括精神分裂症，但迄今为止，还没有一种成功的化合物可以用于任何疾病。尽管很难评估所有临床失败的原因，但疗效不佳是主要原因之一。开发更具选择性的化合物可能会为饱受折磨的精神分裂症患者带来成功的化合物。
本文研究了在临床前研究和临床试验中，α7 烟碱受体的新型激动剂和正变构调节剂。我们的搜索包括使用 SciFinder、Google 和 clinicaltrials.gov，搜索日期为 2015 年至现在。
研究人员必须重新思考他们的方法，应该更仔细地研究新化合物的选择性以及如何解决转化差距。也许新的正变构调节剂可以帮助最小化受体脱敏和选择性特征，这可能是精神分裂症中 α7 nAChR 的一个前进方向。
