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

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