Sulfonium as a Surrogate for Ammonium: A New α7 Nicotinic Acetylcholine Receptor Partial Agonist with Desensitizing Activity

J Med Chem. 2017 Sep 28;60(18):7928-7934. doi: 10.1021/acs.jmedchem.7b00875. Epub 2017 Sep 14.

Abstract

Weak partial agonists that promote a desensitized state of the α7 nicotinic acetylcholine receptor (nAChR) have been associated with anti-inflammatory effects. Exemplar compounds feature a tertiary or quaternary ammonium group. We report the synthesis, structure, and electrophysiological evaluation of 1-ethyl-4-phenylthiomorpholin-1-ium triflate, a weak partial agonist with a sulfonium isostere of the ammonium pharmacophore. These results offer new insights in understanding nAChR-ligand interactions and provide a new chemical space to target the α7 nAChR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ammonium Compounds / chemical synthesis
  • Ammonium Compounds / chemistry
  • Ammonium Compounds / pharmacology
  • Animals
  • Humans
  • Models, Molecular
  • Morpholines / chemical synthesis
  • Morpholines / chemistry*
  • Morpholines / pharmacology*
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / chemistry*
  • Nicotinic Agonists / pharmacology*
  • Onium Compounds / chemical synthesis
  • Onium Compounds / chemistry*
  • Onium Compounds / pharmacology*
  • Sulfonium Compounds / chemical synthesis
  • Sulfonium Compounds / chemistry*
  • Sulfonium Compounds / pharmacology*
  • Xenopus laevis
  • alpha7 Nicotinic Acetylcholine Receptor / agonists*
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism

Substances

  • 1-ethyl-4-phenylthiomorpholin-1-ium
  • Ammonium Compounds
  • Morpholines
  • Nicotinic Agonists
  • Onium Compounds
  • Sulfonium Compounds
  • alpha7 Nicotinic Acetylcholine Receptor