Department of Biotechnology, National Institute of Technology Raipur, Raipur, India.
Department of Biochemistry, North-Eastern Hill University, Shillong, India.
J Pharm Pharmacol. 2018 Aug;70(8):985-993. doi: 10.1111/jphp.12919. Epub 2018 Apr 16.
Alzheimer's disease (AD) has become the primary cause of dementia. It shows a progressive cognitive dysfunction with degenerating neurons. Acetylcholine receptors (AChRs) propagate the cognitive ability and it consists of two primary members namely muscarinic (mAChRs) and nicotinic receptors (nAChRs). Where mAChRs is G-protein coupled receptor, (nAChRs) are ligand-gated ion channels. The conventional therapeutic regimen for AD consists of three acetylcholinestearse inhibitors while a single NMDA receptor antagonist. Researchers around the globe are developing new and modifying the existing AChRs agonists to develop lead candidates with lower risk to benefit ratio where benefits clearly outweigh the adverse events.
We have searched PubMed, MEDLINE, Google scholar, Science Direct and, Web of Science with keywords "Muscarinic/Nicotinic acetylcholine receptor, agonists and, AD". The literature search included articles written in English. Scientific relevance for clinical studies, basic science studies is eligibility criteria for articles referred in this paper. M1 is the primary muscarinic subtype while α7 is the primary nAChR subtype that is responsible for cognition and memory and these two have been the major recent experimental targets for mAChR agonist strategy.
The last cholinergic receptor agonist to enter phase 3 trial was EVP-6124 (Enceniclin) but was withdrawn due to severe gastrointestinal adverse effects. We aim to present an overview of the efforts and achievements in targeting Muscarinic and Nicotinic acetylcholine receptor in the current review for development of better AD therapeutics.
阿尔茨海默病（AD）已成为痴呆的主要原因。它表现为进行性认知功能障碍，神经元退化。乙酰胆碱受体（AChRs）传播认知能力，它由两个主要成员组成，即毒蕈碱（mAChRs）和烟碱受体（nAChRs）。mAChRs 是 G 蛋白偶联受体，（nAChRs）是配体门控离子通道。AD 的常规治疗方案包括三种乙酰胆碱酯酶抑制剂和一种 NMDA 受体拮抗剂。全球研究人员正在开发新的和修改现有的 AChRs 激动剂，以开发风险效益比更低的候选药物，其中收益明显超过不良事件。
我们在 PubMed、MEDLINE、Google Scholar、Science Direct 和 Web of Science 上使用了“毒蕈碱/烟碱乙酰胆碱受体、激动剂和 AD”等关键词进行了搜索。文献检索包括英文撰写的文章。本文所引用的文章的入选标准是对临床研究和基础科学研究具有科学相关性。M1 是主要的毒蕈碱亚型，α7 是主要的 nAChR 亚型，负责认知和记忆，这两个亚型是 mAChR 激动剂策略的主要近期实验靶点。
最后一种进入 3 期试验的胆碱能受体激动剂是 EVP-6124（Enceniclin），但由于严重的胃肠道不良反应而被撤回。我们旨在在当前综述中概述针对毒蕈碱和烟碱乙酰胆碱受体的努力和成就，以开发更好的 AD 治疗方法。
