Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites

J Med Chem. 2006 Jun 1;49(11):3421-5. doi: 10.1021/jm060257t.

Abstract

We describe herein the development of novel huperzine A-tacrine hybrids characterized by 3-methylbicyclo[3.3.1]non-3-ene scaffolds. These compounds were specifically designed to establish tight interactions, through different binding modes, with the midgorge recognition sites of human acetylcholinesterase (hAChE: Y72, D74) and human butyrylcholinesterase (hBuChE: N68, D70) and their catalytic or peripheral sites. Compounds 5a-c show a markedly improved biological profile relative to tacrine and huperzine A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Alkaloids
  • Binding Sites
  • Butyrylcholinesterase / chemistry*
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Humans
  • Models, Molecular
  • Protein Binding
  • Sesquiterpenes / chemical synthesis*
  • Sesquiterpenes / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tacrine / chemical synthesis*
  • Tacrine / chemistry

Substances

  • Alkaloids
  • Cholinesterase Inhibitors
  • Sesquiterpenes
  • huperzine A
  • Tacrine
  • Acetylcholinesterase
  • Butyrylcholinesterase