Development of novel 4‐arylpyridin‐2‐one and 6‐arylpyrimidin‐4‐one positive allosteric modulators of the M1 muscarinic acetylcholine receptor

Scammells, P. J. et al. (2021) Development of novel 4‐arylpyridin‐2‐one and 6‐arylpyrimidin‐4‐one positive allosteric modulators of the M1 muscarinic acetylcholine receptor. ChemMedChem, 16(1), pp. 216-233. (doi: 10.1002/cmdc.202000540) (PMID:32851779)

Abstract

This study investigated the structure‐activity relationships of 4‐phenylpyridin‐2‐one and 6‐phenylpyrimidin‐4‐one muscarinic M1 acetylcholine receptor (M1 mAChRs) positive allosteric modulators (PAMs). The presented series focuses on modifications to the core and top motif of the reported leads, MIPS1650 (1) and MIPS1780 (2). Profiling of our novel analogues showed that these modifications result in more nuanced effects on the allosteric properties compared to our previous compounds with alterations to the biaryl pendant. Further pharmacological characterisation of the selected compounds in radioligand binding, IP1 accumulation and β‐arrestin 2 recruitment assays demonstrated that despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM 7f is a potential lead candidate for further development of peripherally‐restricted M1 PAMs, due to its lower blood‐brain‐barrier (BBB) permeability and improved exposure in the periphery compared to lead 2.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Khajehali, Dr Elham and Tobin, Andrew
• Authors: Scammells, P. J., Jörg, M., Khajehali, E., van der Westhuizen, E. T., Choy, K.H. C., Shackleford, D., Tobin, A. B., Sexton, P. M., Valant, C., Capuano, B., and Christopoulos, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: ChemMedChem
• Publisher: Wiley
• ISSN: 1860-7179
• ISSN (Online): 1860-7187
• Published Online: 26 August 2020
• Copyright Holders: Copyright © 2020 Wiley-VCH GmbH
• First Published: First published in ChemMedChem 16(1): 216-233
• Publisher Policy: Reproduced in accordance with the publisher copyright policy

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
173304		Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical Efficacy	Andrew Tobin	Wellcome Trust (WELLCOTR)	201529/Z/16/Z	MCSB - Molecular Pharmacology