6-Phenylpyrimidin-4-ones as positive allosteric modulators at the M1 mAChR: the determinants of allosteric activity

Jörg, M. et al. (2019) 6-Phenylpyrimidin-4-ones as positive allosteric modulators at the M1 mAChR: the determinants of allosteric activity. ACS Chemical Neuroscience, 10(3), pp. 1099-1114. (doi: 10.1021/acschemneuro.8b00613) (PMID:30547573)

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Abstract

Targeting allosteric sites of the M1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer’s disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M1 mAChR PAMs.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Khajehali, Dr Elham and Tobin, Andrew
Authors: Jörg, M., van der Westhuizen, E. T., Khajehali, E., Burger, W. A. C., White, J. M., Choy, K. H. C., Tobin, A. B., Sexton, P. M., Valant, C., Capuano, B., Christopoulos, A., and Scammells, P. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:ACS Chemical Neuroscience
Publisher:American Chemical Society
ISSN:1948-7193
ISSN (Online):1948-7193
Published Online:14 December 2018

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173304Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOTR)201529/Z/16/ZMCSB - Molecular Pharmacology