2. Academic Validation
  3. Discovery of 2-Methyl-5-(1 H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders

Discovery of 2-Methyl-5-(1 H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders

  • J Med Chem. 2024 Jul 18. doi: 10.1021/acs.jmedchem.4c01207.
Boqun Liu 1,  Geoff Thompson 2,  Manuela Jörg 1,  Nicholas Barnes 2,  David M Thal 2 3,  Arthur Christopoulos 2 3 4,  Ben Capuano 1,  Celine Valant 2 3,  Peter J Scammells 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 2 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 3 Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • 4 Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
PMID: 39023902 DOI: 10.1021/acs.jmedchem.4c01207
Abstract

The M4 Muscarinic Acetylcholine Receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M4 mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M4 mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (GoB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M4 PAMs were assessed for their ability to modulate ACh-mediated β-arrestin recruitment and revealed 4 distinct clusters of M4 PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward β-arrestin recruitment (23i). These novel M4 chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and β-arrestin pathways in neurocognitive disorders.

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