Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

Bradley, S. J. et al. (2018) Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes. Molecular Pharmacology, 93(6), pp. 645-656. (doi: 10.1124/mol.118.111872) (PMID:29695609) (PMCID:PMC5963591)

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The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Brooke, Simon and Dwomoh, Dr Louis and Molloy, Mr Colin and Bradley, Dr Sophie and Thompson, Ms Karen and Tobin, Andrew
Authors: Bradley, S. J., Molloy, C., Bundgaard, C., Mogg, A. J., Thompson, K. J., Dwomoh, L., Sanger, H. E., Crabtree, M. D., Brooke, S. M., Sexton, P. M., Felder, C. C., Christopoulos, A., Broad, L. M., Tobin, A. B., and Langmead, C. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Molecular Pharmacology
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN (Online):1521-0111
Published Online:25 April 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Molecular Pharmacology 93(6): 645-656
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
750161Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOTR)201529/Z/16/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY
750711MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.Andrew TobinMedical Research Council (MRC)MR/P019366/1RI MOLECULAR CELL & SYSTEMS BIOLOGY