Daniel J Foster, Derrick L Choi, P Jeffrey Conn, Jerri M Rook

Alzheimer's disease (AD) and schizophrenia (SZ) are neurological disorders with overlapping symptomatology, including both cognitive deficits and behavioral disturbances. Current clinical treatments for both disorders have limited efficacy accompanied by dose-limiting side effects, and ultimately fail to adequately address the broad range of symptoms observed. Novel therapeutic options for AD and SZ are needed to better manage the spectrum of symptoms with reduced adverse-effect liability. Substantial evidence suggests that activation of muscarinic acetylcholine receptors (mAChRs) has the potential to treat both cognitive and psychosis-related symptoms associated with numerous central nervous system (CNS) disorders. However, use of nonselective modulators of mAChRs is hampered by dose-limiting peripheral side effects that limit their clinical utility. In order to maintain the clinical efficacy without the adverse-effect liability, efforts have been focused on the discovery of compounds that selectively modulate the centrally located M1 and M4 mAChR subtypes. Previous drug discovery attempts have been thwarted by the highly conserved nature of the acetylcholine site across mAChR subtypes. However, current efforts by our laboratory and others have now focused on modulators that bind to allosteric sites on mAChRs, allowing these compounds to display unprecedented subtype selectivity. Over the past couple of decades, the discovery of small molecules capable of selectively targeting the M1 or M4 mAChR subtypes has allowed researchers to elucidate the roles of these receptors in regulating cognitive and behavioral disturbances in preclinical animal models. Here, we provide an overview of these promising preclinical and clinical studies, which suggest that M1- and M4-selective modulators represent viable novel targets with the potential to successfully address a broad range of symptoms observed in patients with AD and SZ.