Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: subnanomolar dual binding site acetylcholinesterase inhibitors

J Med Chem. 2005 Mar 24;48(6):1701-4. doi: 10.1021/jm0496741.

Abstract

A series of huprine-tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC(50) values in the subnanomolar and low nanomolar range, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / chemistry
  • Animals
  • Binding Sites
  • Butyrylcholinesterase / chemistry
  • Cattle
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Humans
  • Structure-Activity Relationship
  • Tacrine / analogs & derivatives*
  • Tacrine / chemical synthesis*
  • Tacrine / chemistry

Substances

  • Aminoquinolines
  • Cholinesterase Inhibitors
  • Heterocyclic Compounds, 4 or More Rings
  • huprine X
  • huprine Y
  • Tacrine
  • Acetylcholinesterase
  • Butyrylcholinesterase