Synthesis and binding studies of epibatidine analogues as ligands for the nicotinic acetylcholine receptors

Eur J Med Chem. 2006 May;41(5):640-50. doi: 10.1016/j.ejmech.2006.01.015. Epub 2006 Mar 20.

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are transmembrane ligand-gated ion channels. Recent research demonstrated that selective nAChR ligands may have therapeutic potential in a number of CNS diseases and disorders. The alkaloid epibatidine is a highly potent non-opioid analgesic and nAChR agonist, but too toxic to be a useful ligand. To develop ligands selective for distinct nAChR subtypes and with reduced toxicity, a series of epibatidine and homoepibatidine analogues were synthesized. (+/-)-8-Methyl-3-(pyridin-3-yl)-8-azabicyclo[3,2,1]oct-2-ene, showed high affinity towards alpha4beta2 (Ki=2 nM), subtype selectivity (alpha4beta2/alpha7 affinity ratio>100) and relatively low toxicity in mice and can be labeled with 11C and 18F as positron emission tomography (PET) tracers for imaging of nAChRs.

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism*
  • Bridged Bicyclo Compounds, Heterocyclic / toxicity
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Mice
  • Molecular Structure
  • Neurons / drug effects
  • Neurons / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / metabolism*
  • Pyridines / toxicity
  • Rats
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Ligands
  • Pyridines
  • Receptors, Nicotinic
  • epibatidine