Affordable Access

deepdyve-link
Publisher Website

6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M1 mAChR: The Determinants of Allosteric Activity.

Authors
  • Jörg, Manuela
  • van der Westhuizen, Emma T
  • Khajehali, Elham
  • Burger, Wessel A C
  • White, Jonathan M1
  • Choy, Kwok H C
  • Tobin, Andrew B2
  • Sexton, Patrick M
  • Valant, Celine
  • Capuano, Ben
  • Christopoulos, Arthur
  • Scammells, Peter J
  • 1 Bio21 Molecular Science and Biotechnology Institute , The University of Melbourne , 30 Flemington Road , Parkville 3010 , VIC , Australia. , (Australia)
  • 2 Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences , University of Glasgow , Glasgow G12 8QQ , United Kingdom. , (United Kingdom)
Type
Published Article
Journal
ACS Chemical Neuroscience
Publisher
American Chemical Society
Publication Date
Mar 20, 2019
Volume
10
Issue
3
Pages
1099–1114
Identifiers
DOI: 10.1021/acschemneuro.8b00613
PMID: 30547573
Source
Medline
Keywords
Language
English
License
Unknown

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.

Report this publication

Statistics

Seen <100 times