Muscarinic M1 and M4 receptors (agonist)

Class

Oral, extended-release, fixed-dose combination of the investigational M1/M4-preferring muscarinic receptor agonist ML-007, co-formulated with a peripherally acting muscarinic antagonist (PAC) intended to limit off-target peripheral cholinergic side effects.

Pathway

Activation of both M1 and M4 muscarinic receptor subtypes in the CNS; preclinical knockout studies indicate both subtypes contribute to antipsychotic-like activity across multiple psychosis models.

Muscarinic acetylcholine receptors are G protein-coupled receptors that mediate the actions of acetylcholine throughout the central and peripheral nervous systems. Five subtypes exist (M1–M5), each coupling to distinct intracellular signaling pathways and showing different tissue distributions. M1 and M4 are enriched in brain regions implicated in cognition, mood, and psychosis, including the striatum, hippocampus, and cortex. Preclinical genetic and pharmacological studies indicate that stimulating M1 and M4 can produce antipsychotic-like effects without directly blocking dopamine D2 receptors, the mechanism shared by essentially all approved antipsychotic medicines. This offers a potential route to treating psychosis through a different pathway, one that may address symptoms poorly responsive to dopamine-based drugs and could avoid some of the motor and metabolic effects associated with D2 blockade. Because muscarinic receptors are also densely expressed outside the brain, in the gut, bladder, cardiovascular system, and glands, broadly acting agonists risk causing peripheral cholinergic side effects. Pairing a brain-active M1/M4 agonist with an antagonist that does not cross the blood-brain barrier is a strategy intended to blunt those peripheral effects while preserving central activity, illustrating how selectivity and formulation choices can be used to widen a therapeutic window.