Novel pyridyl ring C5 substituted analogues of epibatidine and 3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (A-84543) as highly selective agents for neuronal nicotinic acetylcholine receptors containing beta2 subunits

J Med Chem. 2005 Mar 24;48(6):1721-4. doi: 10.1021/jm0492406.


Introduction of a hydrophobic or hydrogen-bonding alkynyl group into the C5 position of the pyridyl ring of epibatidine and A-84543 significantly increased the selectivity for neuronal nicotinic acetylcholine receptors (nAChRs) containing beta2 subunits over nAChRs containing beta4 subunits (K(i) ratio up to 92000-fold). Our data indicate that the extracellular domains of the nAChRs are sufficiently different to allow for the design of novel ligands with high affinity and selectivity for the nAChR subtypes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Ligands
  • Models, Molecular
  • Neurons / metabolism*
  • Protein Subunits / chemistry
  • Protein Subunits / drug effects
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Rats
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / drug effects*


  • 3-(2-(pyrrolidinyl)methoxy)pyridine
  • Bridged Bicyclo Compounds, Heterocyclic
  • Ligands
  • Protein Subunits
  • Pyridines
  • Pyrrolidines
  • Receptors, Nicotinic
  • epibatidine