AI Article Synopsis
- Selective activation of the M4 subtype of muscarinic acetylcholine receptors (mAChRs) might offer therapeutic benefits for neurological disorders while reducing side effects common with nonselective activation.
- Challenges in developing M4-selective agonists stem from the high structural similarity among mAChR subtypes, making it difficult to target M4 specifically.
- This study presents newly discovered M4 subtype-selective agonists that utilize novel carbamate isosteres, highlighting important structural features that aid in selective activation and detailing how these compounds interact with the receptor.
Article Abstract
It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580797 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.9b00106 | DOI Listing |
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