Discovery, Optimization, and Characterization of Novel Subtype-Selective Muscarinic Acetylcholine Receptor M4 and M5 Positive Allosteric Modulators

Abstract

There exist five subtypes of the muscarinic acetylcholine receptor (M1-M5), which are differentially expressed throughout the body and play important roles in numerous physiological processes, including autonomic functions, motor control, cognition, reward, and sleep, among others. A historic lack of small molecules possessing high subtype-selectivity has hampered basic neurobiological research into the roles of each subtype in the central nervous system and has precluded successful therapeutic development of muscarinic ligands targeting a particular receptor subtype. Functional cell-based screening in conjunction with medicinal chemistry techniques were performed in order to discover highly subtype-selective allosteric ligands for M1, M4, and M5. Multiple series of M1 positive allosteric modulators, M1 allosteric agonists, M1 antagonists, M4 positive allosteric modulators, and the first series of selective M5 positive allosteric modulators were successfully discovered, optimized, and characterized.