Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors

Bioorg Med Chem. 2008 Aug 1;16(15):7450-6. doi: 10.1016/j.bmc.2008.06.022. Epub 2008 Jun 14.

Abstract

A number of mono- and bis-quaternary ammonium salts, containing edrophonium-like and coumarin moieties tethered by an appropriate linker, proved to be highly potent and selective dual binding site acetylcholinesterase inhibitors with good selectivity over butyrylcholinesterase. Homobivalent bis-quaternary inhibitors 11 and 12, differing by only one methylene unit in the linker, were the most potent and selective inhibitors exhibiting a sub-nanomolar affinity (IC(50)=0.49 and 0.17 nM, respectively) and a high butyryl-/acetylcholinesterase affinity ratio (SI=1465 and 4165, respectively). The corresponding hetero-bivalent coumarinic inhibitors 13 and 14 were also endowed with excellent inhibitory potency but a lower AChE selectivity (IC(50)=2.1 and 1.0 nM, and SI=505 and 708, respectively). Docking simulations enabled clear interpretation of the structure-affinity relationships and detection of key binding interactions at the primary and peripheral AChE binding sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cattle
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology*
  • Computer Simulation
  • Drug Design
  • Edrophonium / chemistry*
  • Edrophonium / pharmacology*
  • Horses
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Edrophonium
  • Acetylcholinesterase
  • Butyrylcholinesterase