Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres.
Basic Information
ID: ALA4304767
Journal: ACS Med Chem Lett
Title: Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres.
Authors: Yang Q, Lachapelle EA, Kablaoui NM, Webb D, Popiolek M, Grimwood S, Kozak R, O'Connor RE, Lazzaro JT, Butler CR, Zhang L.
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.
CiteXplore: 31223452
DOI: 10.1021/acsmedchemlett.9b00106
Patent ID: ┄