Abstract
The methyl group in cis stereochemical relationship with the basic chain of all pentatomic cyclic analogues of ACh is crucial for the agonist activity at mAChR. Among these only cevimeline (1) is employed in the treatment of xerostomia associated with Sjögren's syndrome. Here we demonstrated that, unlike 1,3-dioxolane derivatives, in the 1,4-dioxane series the methyl group is not essential for the activation of mAChR subtypes. Docking studies, using the crystal structures of human M2 and rat M3 receptors, demonstrated that the 5-methylene group of the 1,4-dioxane nucleus of compound 10 occupies the same lipophilic pocket as the methyl group of the 1,3-dioxolane 4.
Original language | English (US) |
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Pages (from-to) | 3255-3259 |
Number of pages | 5 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 24 |
Issue number | 15 |
DOIs | |
State | Published - Aug 1 2014 |
Externally published | Yes |
Keywords
- 1,4-Dioxane nucleus
- Acetylcholine muscarinic receptors
- Docking studies
- Muscarinic agonists
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry