Probing Structural Requirements of Positive Allosteric Modulators of the M₄ Muscarinic Receptor

The M₄ mAChR is implicated in several CNS disorders and possesses an allosteric binding site for which ligands modulating the affinity and/or efficacy of ACh may be exploited for selective receptor targeting. We report the synthesis of a focused library of putative M₄ PAMs derived from VU0152100 and VU10005. These compounds investigate the pharmacological effects of previously identified methoxy and fluoro substituents, providing useful estimates of affinity (<i>K</i>_B), cooperativity (αβ), and direct agonist properties (τ_B)