Optimization and characterization of muscarinic acetylcholine receptor M4 positive allosteric modulators

Abstract

Acetycholine is one of the major neurotransmitters that regulate various functions ranging from cognition to motor. It activates muscarinic acetylcholine receptors (mAChRs), which are highly expressed in the brain. mAChRs are implicated in many physiological processes and neurological disorders; therefore, these receptors are appealing targets for the regulation of acetylcholine functions. Due to high structural homology across the five mAChR subtypes, developing tool compounds that are subtype selectivity is cumbersome. We are interested in enhancing selectivity and receptor activity of the muscarinic acetylcholine receptor subtype M4 by positive allosteric modulation (PAM). Because positive allosteric modulators mimic basal response and are only efficacious in the presence of the endogenous agonist, they have lower off-target toxicity and allow for higher subtype selectivity. Using iterative parallel library synthesis, we improve specificity, potency, and pharmacology profile of our recently published M4 PAM, VU0152100.