Systematic development of high affinity bis(ammonio)alkane-type allosteric enhancers of muscarinic ligand binding

J Med Chem. 2003 Mar 13;46(6):1031-40. doi: 10.1021/jm021017q.


Bis(ammonio)alkane compounds carrying lateral phthalimidopropyl substituents on the nitrogen atoms belong to the archetypal muscarinic allosteric agents. Herein, a series of symmetrical and nonsymmetrical compounds was synthesized in which the phthalimide residues were replaced by differently substituted imide moieties. The allosteric action was measured in porcine heart muscarinic M(2) receptors using [(3)H]N-methylscopolamine (NMS) as a ligand for the orthosteric receptor site in equilibrium binding and dissociation experiments. 1,8-Naphthalimido residues conferred an up to 100-fold gain in affinity leading into the low nanomolar range, while the inhibition of NMS binding was maintained. Additional propyl chain methylation was accompanied by an allosteric elevation of orthosteric ligand binding. In general, the gain in allosteric activity achieved by ring variation plus propyl chain methylation on one side of the molecule could not be augmented by symmetrical variations. The elevation of the ligand binding can be explained by different quantitative structure-activity relationships for the affinities to the free and the orthoster-liganded receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkanes / chemical synthesis*
  • Alkanes / chemistry
  • Alkanes / pharmacology
  • Allosteric Regulation
  • Animals
  • In Vitro Techniques
  • Ligands
  • Myocardium / metabolism
  • Phthalic Acids / chemical synthesis*
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology
  • Quantitative Structure-Activity Relationship
  • Quaternary Ammonium Compounds / chemical synthesis*
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacology
  • Radioligand Assay
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / metabolism*
  • Regression Analysis
  • Swine


  • Alkanes
  • Ligands
  • Phthalic Acids
  • Quaternary Ammonium Compounds
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic