Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal

ABSTRACT

Introduction

Successful phase 3 trials of KarXT in people with schizophrenia herald a new era of treating the disorder with drugs that do not target the dopamine D2 receptor. The active component of KarXT is xanomeline, a muscarinic (CHRM) M1 and M4 agonist, making muscarinic receptors a viable target for treating schizophrenia.

Areas Covered

This review covers the process of taking drugs that activate the muscarinic M1 and M4 receptors from conceptualization to the clinic and details the mechanisms by which activating the CHRM1 and 4 can affect the broad spectrum of symptoms experienced by people with schizophrenia.

Expert Opinion

Schizophrenia is a syndrome which means drugs that activate muscarinic M1 and M4 receptors, as was the case for antipsychotic drugs acting on the dopamine D2 receptor, will not give optimal outcomes in everyone within the syndrome. Thus, it would be ideal to identify people who are responsive to drugs activating the CHRM1 and 4. Given knowledge of the actions of these receptors, it is possible treatment non-response could be restricted to sub-groups within the syndrome who have deficits in cortical CHRM1 or those with one of the cognitive endophenotypes that may be identifiable by changes in the blood transcriptome.

KEYWORDS:

• Schizophrenia
• muscarinic receptors
• sub-grouping
• receptor activation
• KarXT

Article highlights

• Evidence implicating the muscarinic M1 and M4 receptors in the molecular pathology of schizophrenia are comprehensively reviewed.

• The progress in developing drugs that target muscarinic M1 and M4 receptors as a treatment for schizophrenia is detailed.

• Findings using mice lacking muscarinic M1 or M4 receptors are detailed as they gave the first specific indications of the role of these receptors in CNS function.

• The use of allosteric modulators at the muscarinic M1 or M4 receptor to understand the role of these receptors in CNS function is summarized.

• The significance of an intermediate phenotype within the syndrome of schizophrenia identified because of the group has a marked loss of muscarinic M1 and M4 receptor is considered.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

There was no specific funding body that made a significant contribution to the writing of this review.