Abstract:
:Among the muscarinic acetylcholine receptor (mAChR) subtypes, the M4 receptor has been investigated as a promising drug target for the treatment of schizophrenia. These investigations have been based on findings from M4-deficient mice studies as well as on the results of a clinical trial that used xanomeline, an M1/M4 mAChRs-preferring agonist. Both orthosteric agonists and positive allosteric modulators of M4 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 M4 mAChR activators, orthosteric agonists, and positive allosteric modulators based on M4 mAChR structural information and structure-activity relationship studies. These findings indicate that selective M4 mAChR activators are promising potential therapeutic agents for several central nervous system conditions.
journal_name
Chem Pharm Bull (Tokyo)journal_title
Chemical & pharmaceutical bulletinauthors
Takai K,Enomoto Tdoi
10.1248/cpb.c17-00413subject
Has Abstractpub_date
2018-01-01 00:00:00pages
37-44issue
1eissn
0009-2363issn
1347-5223journal_volume
66pub_type
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