Discovery and Development of Muscarinic Acetylcholine M4 Activators as Promising Therapeutic Agents for CNS Diseases

Among the muscarinic acetylcholine receptor (mAChR) subtypes, the M-4 receptor has been investigated as a promising drug target for the treatment of schizophrenia. These investigations have been based on findings from M-4-deficient mice studies as well as on the results of a clinical trial that used xanomeline, an M-1/M-4 mAChRs-preferring agonist. Both orthosteric agonists and positive allosteric modulators of M-4 mAChR have been reported as promising ligands that not only have antipsychotic effects, but can also improve cognitive impairment and motor dysfunction. However, challenges remain due to the high homology of the orthosteric binding site among all muscarinic receptors. In this review, we summarize our approach to the identification of M-4 mAChR activators, orthosteric agonists, and positive allosteric modulators based on M-4 mAChR structural information and structure activity relationship studies. These findings indicate that selective M-4 mAChR activators are promising potential therapeutic agents for several central nervous system conditions.