小柯机器人

英国格拉斯哥大学Andrew B. Tobin、剑桥大学Malcolm Weir等研究人员合作设计出具有治疗阿尔茨海默病潜力的毒蕈碱M1受体激动剂。2021年11月24日，国际知名学术期刊《细胞》发表了这一成果。

研究人员希望设计出一种具有良好耐受性的M1-毒蕈碱乙酰胆碱（M1）受体激动剂，通过采取逐步转化的方法，从原子结构、基于细胞/组织的检测、临床前物种的评估、临床安全测试，最后在人类的记忆中心建立活性，来缓解认知障碍。通过这种方法，研究人员合理地将最佳特性，包括选择性和部分激动性，设计成HTL9936，这是一个治疗阿尔茨海默病记忆丧失的潜在药物。更广泛地说，这表明了一种从结构到临床的转化策略。

据悉，目前治疗阿尔茨海默病的方法是通过抑制乙酰胆碱酯酶来防止乙酰胆碱的分解，从而纠正有缺陷的胆碱能传递，然而这些方法的临床疗效有限。另一种方法是直接激活负责学习和记忆的胆碱能受体。M1受体是可选择的靶标，但一直受到不良影响的阻碍。

附：英文原文

Title: From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer’s disease

Author: Alastair J.H. Brown, Sophie J. Bradley, Fiona H. Marshall, Giles A. Brown, Kirstie A. Bennett, Jason Brown, Julie E. Cansfield, David M. Cross, Chris de Graaf, Brian D. Hudson, Louis Dwomoh, Joo M. Dias, James C. Errey, Edward Hurrell, Jan Liptrot, Giulio Mattedi, Colin Molloy, Pradeep J. Nathan, Krzysztof Okrasa, Greg Osborne, Jayesh C. Patel, Mark Pickworth, Nathan Robertson, Shahram Shahabi, Christoffer Bundgaard, Keith Phillips, Lisa M. Broad, Anushka V. Goonawardena, Stephen R. Morairty, Michael Browning, Francesca Perini, Gerard R. Dawson, John F.W. Deakin, Robert T. Smith, Patrick M. Sexton, Julie Warneck, Mary Vinson, Tim Tasker, Benjamin G. Tehan, Barry Teobald, Arthur Christopoulos, Christopher J. Langmead, Ali Jazayeri, Robert M. Cooke, Prakash Rucktooa, Miles S. Congreve, Malcolm Weir, Andrew B. Tobin

Issue&Volume: 2021/11/24

Abstract: Current therapies for Alzheimer’s disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936—a potential candidate for the treatment of memory loss in Alzheimer’s disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

DOI: 10.1016/j.cell.2021.11.001

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01316-7