The potential of muscarinic M₁ and M₄ receptor activators for the treatment of cognitive impairment associated with schizophrenia

Cognitive impairment is a core symptom of schizophrenia and a major determinant of poor long-term functional outcomes. Despite considerable efforts, we do not yet have any approved pharmacological treatments for cognitive impairment associated with schizophrenia (CIAS). A combination of advances in pre-clinical research and recent clinical trial findings have led to a resurgence of interest in the cognition-enhancing potential of novel muscarinic acetylcholine receptor (mAChR) agonists in schizophrenia. This article provides an overview of the scientific rationale for targeting M₁ and M₄ mAChRs. We describe the evolution of neuroscience research on these receptors since early drug discovery efforts focused on the mAChR agonist xanomeline. This work has revealed that M₁ and M₄ mAChRs are highly expressed in brain regions that are implicated in cognition. The functional significance of M₁ and M₄ mAChRs has been extensively characterized in animal models via use of selective receptor subtype compounds through neuronal and non-neuronal mechanisms. Recent clinical trials of a dual M₁/M₄ mAChR agonist show promising, replicable evidence of potential pro-cognitive effects in schizophrenia, with several other mAChR agonists in clinical development.