From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease
| Autor: | 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, João 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 |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Models Molecular Primates Aging Blood Pressure CHO Cells Molecular Dynamics Simulation Article Cricetulus Dogs Alzheimer Disease Heart Rate Animals Humans Donepezil Amino Acid Sequence Aged Aged 80 and over Receptor Muscarinic M1 Electroencephalography Rats Mice Inbred C57BL Disease Models Animal HEK293 Cells Structural Homology Protein Drug Design Nerve Degeneration Female Cholinesterase Inhibitors Crystallization Signal Transduction |
| Zdroj: | Trends Pharmacol Sci |
| ISSN: | 1097-4172 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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