Skip to main content

Research Repository

Advanced Search

Assessment of the molecular mechanisms of action of novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one allosteric modulators at the M1 muscarinic acetylcholine receptors

van der Westhuizen, Emma T.; Spathis, Arthur; Khajehali, Elham; Jörg, Manuela; Mistry, Shailesh N.; Capuano, Ben; Tobin, Andrew B.; Sexton, Patrick M.; Scammells, Peter J.; Valant, Celine; Christopoulos, Arthur

Assessment of the molecular mechanisms of action of novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one allosteric modulators at the M1 muscarinic acetylcholine receptors Thumbnail


Authors

Emma T. van der Westhuizen

Arthur Spathis

Elham Khajehali

Manuela Jörg

Ben Capuano

Andrew B. Tobin

Patrick M. Sexton

Peter J. Scammells

Celine Valant

Arthur Christopoulos



Abstract

Positive allosteric modulators (PAMs) that target the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) are potential treatments for cognitive deficits in conditions such as Alzheimer's disease and schizophrenia. We recently reported novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one M1 mAChR PAMs with the potential to display different modes of positive allosteric modulation and/or agonism (Mistry et al., 2016), but their molecular mechanisms of action remain undetermined. The current study compared the pharmacology of three such novel PAMs with the prototypical first-generation PAM, BQCA, in a recombinant Chinese hamster ovary (CHO) cell line stably expressing the human M1 mAChR. Interactions between the orthosteric agonists and the novel PAMs or BQCA suggested their allosteric effects were solely governed by modulation of agonist affinity. The greatest degree of positive co-operativity was observed with higher efficacy agonists, whereas minimal potentiation was observed when the modulators were tested against the lower efficacy agonist, xanomeline. Each PAM was investigated for its effects on the endogenous agonist, ACh, on three different signalling pathways, (ERK1/2 phosphorylation, IP1 accumulation and β-arrestin-2 recruitment), revealing that the allosteric potentiation generally tracked with the efficiency of stimulus-response coupling and that there was little pathway bias in the allosteric effects. Thus, despite the identification of novel allosteric scaffolds targeting the M1 mAChR, the molecular mechanism of action of these compounds is largely consistent with a model of allostery previously described for BQCA, suggesting that this may be a more generalized mechanism for M1 mAChR PAM effects than previously appreciated.

Citation

van der Westhuizen, E. T., Spathis, A., Khajehali, E., Jörg, M., Mistry, S. N., Capuano, B., Tobin, A. B., Sexton, P. M., Scammells, P. J., Valant, C., & Christopoulos, A. (in press). Assessment of the molecular mechanisms of action of novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one allosteric modulators at the M1 muscarinic acetylcholine receptors. Molecular Pharmacology, https://doi.org/10.1124/mol.118.111633

Journal Article Type Article
Acceptance Date Apr 19, 2018
Online Publication Date Apr 24, 2018
Deposit Date Apr 24, 2018
Publicly Available Date Apr 24, 2018
Journal Molecular Pharmacology
Print ISSN 0026-895X
Electronic ISSN 1521-0111
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1124/mol.118.111633
Keywords Acetylcholine receptors; Allosterism; Alzheimer's Disease; Biased agonism; Cholinergic pharmacology; Cognition; Drug discovery; G protein-coupled receptors (GPCRs); Muscarinic cholinergic receptors; Schizophrenia
Public URL https://nottingham-repository.worktribe.com/output/928187
Publisher URL http://molpharm.aspetjournals.org/content/early/2018/04/24/mol.118.111633
Contract Date Apr 24, 2018

Files





You might also like



Downloadable Citations