Mode of interaction of 1,4-dioxane agonists at the M2 and M3 muscarinic receptor orthosteric sites

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3255-9. doi: 10.1016/j.bmcl.2014.06.020. Epub 2014 Jun 14.

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.

Keywords: 1,4-Dioxane nucleus; Acetylcholine muscarinic receptors; Docking studies; Muscarinic agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Dioxanes / chemistry
  • Dioxanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Muscarinic Agonists / chemistry
  • Muscarinic Agonists / pharmacology*
  • Rats
  • Receptor, Muscarinic M2 / agonists*
  • Receptor, Muscarinic M3 / agonists*
  • Structure-Activity Relationship

Substances

  • Dioxanes
  • Muscarinic Agonists
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • 1,4-dioxane