Dioxane and oxathiane nuclei: suitable substructures for muscarinic agonists

Bioorg Med Chem. 2007 Jan 15;15(2):886-96. doi: 10.1016/j.bmc.2006.10.040. Epub 2006 Oct 21.

Abstract

Muscarinic agonists, bearing 1,4-dioxane and 1,4-oxathiane nuclei, were synthesized and tested to evaluate their potency at M(1)-M(4) muscarinic receptor subtypes. The stereochemical relationship between the 2-side chain and the 6-methyl group plays an important role in drug-receptor interaction, since the cis isomers are more potent than the corresponding trans isomers. However, the latter are able to discriminate between the muscarinic receptor subtypes. Among them compound 5b proves particularly interesting, since it selectively activates the ileal M(3) receptor subtype and is devoid of agonist activity at the others.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dioxanes / chemistry*
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Heart Atria / drug effects
  • Heterocyclic Compounds, 1-Ring / chemical synthesis*
  • Heterocyclic Compounds, 1-Ring / pharmacology*
  • Ileum / drug effects
  • Indicators and Reagents
  • Isomerism
  • Lung / drug effects
  • Magnetic Resonance Spectroscopy
  • Male
  • Models, Molecular
  • Muscarinic Agonists / chemical synthesis*
  • Muscarinic Agonists / pharmacology*
  • Muscle, Smooth / drug effects
  • Rabbits
  • Receptor, Muscarinic M1 / agonists
  • Receptor, Muscarinic M2 / agonists
  • Receptor, Muscarinic M3 / agonists
  • Receptor, Muscarinic M4 / agonists
  • Structure-Activity Relationship
  • Vas Deferens / drug effects

Substances

  • Dioxanes
  • Heterocyclic Compounds, 1-Ring
  • Indicators and Reagents
  • Muscarinic Agonists
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptor, Muscarinic M4
  • oxathiane