| Autor: |
Alastair J. H. Brown, Sophie J. Bradley, Giles A. Brown, Kirstie A. Bennett, Jason Brown, Julie E. Cansfield, David M. Cross, João M. Dias, James C. Errey, Edward Hurrell, Jan Liptrot, Colin Molloy, Pradeep J. Nathan, Krzysztof Okrasa, Greg Osbourne, 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, Fiona H. Marshall, Prakash Rucktooa, Miles S. Congreve, Malcolm Weir, Andrew Tobin |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| DOI: |
10.2139/ssrn.3641933 |
| Popis: |
Current therapies for improving memory in Alzheimer’s disease are focused on correcting for defective cholinergic transmission by increasing acetylcholine levels through inhibition of acetylcholinesterase enzymes. These treatments are however associated with limited clinical efficacy and dose-limiting adverse effects. Here we describe agonist-bound crystal structures of the M1 muscarinic acetylcholine receptor (M1 mAChR) and its application in supporting the rational drug design of a selective M1-orthosteric agonist, HTL0009936. On the basis of pro-cognitive effects across a range of pre-clinical animal models and a favourable safety and toxicology profile HTL0009936 was progressed to first in human trials where the agonist activated central processes corresponding to learning and memory circuitry. Hence, our study not only describes the pharmacological profile of a M1 mAChR agonist with the potential to improve memory in Alzheimer’s disease but also demonstrates how to rationally progress the development of a G protein-coupled receptor ligand from structure to clinical candidate. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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