Synthesis and nicotinic acetylcholine receptor in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues of 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine

J Med Chem. 2012 Jul 26;55(14):6512-22. doi: 10.1021/jm300575y. Epub 2012 Jul 11.


Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines 5b-g, analogues of 3'-(4-nitrophenyl) compound 5a. All compounds had high affinity for α4β2-nAChR and low affinity for α7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at α4β2-, α3β4-, and α7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for α4β2-nAChR over α3β4- and α7-nAChRs. All the analogues were antagonists of nicotine-induced antinociception in the tail-flick test. Molecular modeling docking studies using the agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a-g. In particular, a unique binding mode for 5g was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of 5g for α4β2-nAChR combined with its nAChR functional antagonist properties suggest that 5g will be a valuable pharmacological tool for studying the nAChR and may have potential as a pharmacotherapy for addiction and other central nervous system disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Chemistry Techniques, Synthetic
  • Electrophysiological Phenomena / drug effects
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Nicotinic Agonists / chemical synthesis*
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology*
  • Nicotinic Antagonists / chemical synthesis*
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology*
  • Protein Conformation
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / metabolism*


  • 2-fluoro-3-(4-nitrophenyl)deschloroepibatidine
  • Bridged Bicyclo Compounds, Heterocyclic
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Pyridines
  • Receptors, Nicotinic