Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity

Eur J Med Chem. 2014 Mar 21:75:222-32. doi: 10.1016/j.ejmech.2014.01.032. Epub 2014 Jan 25.

Abstract

In this study, we synthesized and tested in vitro and in vivo two groups of bis(ammonio)alkane-type compounds, 6a-9a and 6b-9b, which incorporate the orthosteric muscarinic agonist iperoxo into a molecular fragment of the M2-selective allosteric modulators W84 and naphmethonium. The agonist potency and efficacy of these hybrid derivatives at M1, M2 and M3 muscarinic receptor subtypes and their anticholinesterase activity were evaluated on isolated tissue preparations. Their analgesic action was then assayed in vivo in the acetic acid writhing test and the occurrence of peripheral and central cholinergic side effects was also determined. The investigated hybrids behaved as potent muscarinic agonists and weak cholinesterase inhibitors. These effects were more pronounced for bisquaternary salts bearing the naphmethonium moiety than for the W84-containing analogs, and resulted in a significant analgesic activity in vivo. A promising profile was displayed by the naphmethonium-related compound 8b, which combined the most potent antinociception among the test compounds with the absence of relevant cholinergic side effects.

Keywords: Alkylbisammonio quaternary salts; Analgesic activity; In vitro pharmacology; In vivo pharmacology; Muscarinic agonists; Muscarinic receptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkanes / chemical synthesis
  • Alkanes / chemistry*
  • Alkanes / pharmacology*
  • Ammonium Compounds / chemical synthesis
  • Ammonium Compounds / chemistry
  • Ammonium Compounds / pharmacology
  • Analgesics / chemical synthesis
  • Analgesics / chemistry*
  • Analgesics / pharmacology*
  • Animals
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Female
  • Guinea Pigs
  • Male
  • Mice
  • Muscarinic Agonists / chemical synthesis
  • Muscarinic Agonists / chemistry*
  • Muscarinic Agonists / pharmacology*
  • Rabbits
  • Rats
  • Rats, Wistar
  • Receptors, Muscarinic / metabolism*

Substances

  • Alkanes
  • Ammonium Compounds
  • Analgesics
  • Cholinesterase Inhibitors
  • Muscarinic Agonists
  • Receptors, Muscarinic