Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors

Abstract

Muscarinic agonists represent a new class of treatments for psychosis with a mechanism distinct from typical and atypical antipsychotics. The muscarinic subtype M₄ has been proposed as the primary mediator of efficacy but results from recent clinical trials with M₄-selective compounds have drawn this hypothesis into question. Instead, activation of both M₁ and M₄ receptor subtypes may be required for robust treatment effects. Here, we characterize the clinical-stage muscarinic agonist ML-007 in preclinical models and explore its therapeutic potential for treating psychosis in schizophrenia and Alzheimer's disease. ML-007 is a potent brain-penetrant agonist at both M₁ and M₄ muscarinic receptors that has demonstrated compelling efficacy across a range of preclinical models of psychosis in schizophrenia including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Moreover, ML-007 is approximately ten-fold more potent than the comparator xanomeline in all animal models. Dose-response experiments in M₁ and M₄ knockout mice reveal that the efficacy of ML-007 is dependent on both M₁ and M₄ receptors. Taken together, our data suggest that both M₁ and M₄ receptors contribute to the potent efficacy of ML-007 in preclinical rodent models of psychosis.