Mode of interaction of 1,4-dioxane agonists at the M2 and M 3 muscarinic receptor orthosteric sites

Fabio Del Bello, Alessandro Bonifazi, Wilma Quaglia, Angelica Mazzolari, Elisabetta Barocelli, Simona Bertoni, Rosanna Matucci, Marta Nesi, Alessandro Piergentili, Giulio Vistoli

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 languageEnglish (US)
Pages (from-to)3255-3259
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number15
DOIs
StatePublished - Aug 1 2014
Externally publishedYes

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

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