Selective allosteric modulation of muscarinic acetylcholine receptors for the treatment of schizophrenia and substance use disorders

Muscarinic acetylcholine receptor (mAChRs) subtypes represent exciting new targets for the treatment of schizophrenia and substance use disorder (SUD). Recent advances in the development of subtype-selective allosteric modulators have revealed promising effects in preclinical models targeting the different symptoms observed in schizophrenia and SUD. M₁ PAMs display potential for addressing the negative and cognitive symptoms of schizophrenia, while M₄ PAMs exhibit promise in treating preclinical models predictive of antipsychotic-like activity. In SUD, there is increasing support for modulation of mesocorticolimbic dopaminergic circuitry involved in SUD with selective M₄ mAChR PAMs or M₅ mAChR NAMs. Allosteric modulators of these mAChR subtypes have demonstrated efficacy in rodent models of cocaine and ethanol seeking, with indications that these ligand may also be useful for other substances of abuse, as well as in various stages in the cycle of addiction. Importantly, allosteric modulators of the different mAChR subtypes may provide viable treatment options, while conferring greater subtype specificity and corresponding enhanced therapeutic index than orthosteric muscarinic ligands and maintaining endogenous temporo-spatial ACh signaling. Overall, subtype specific mAChR allosteric modulators represent important novel therapeutic mechanisms for schizophrenia and SUD.