6'-Methylpyrido[3,4-b]norhomotropane: synthesis and outstanding potency in relation to the alpha4beta2 nicotinic receptor pharmacophore model

Bioorg Med Chem Lett. 2005 Feb 15;15(4):877-81. doi: 10.1016/j.bmcl.2004.12.069.

Abstract

6'-Methylpyrido[3,4-b]norhomotropane [synthesis as the racemate reported here] is more potent at the alpha4beta2 nicotinic receptor than any previous bridged nicotinoid. The two nitrogens and 6'-methyl substituent are superimposable on the two nitrogens and 6-chloro substituent of epibatidine, with the best fit on comparing the chair conformer of the (1R)-pyridonorhomotropane with natural (1R)-epibatidine. In this pharmacophore model, the 6'-methyl substituent may be equivalent to the acetyl methyl of acetylcholine.

Publication types

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

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Nicotine / analogs & derivatives
  • Protein Binding
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Receptors, Nicotinic / chemistry*
  • Structure-Activity Relationship
  • Tropanes / chemical synthesis*
  • Tropanes / chemistry*
  • Tropanes / pharmacology

Substances

  • 6'-methylpyrido(3,4-b)norhomotropane
  • Bridged Bicyclo Compounds, Heterocyclic
  • Pyridines
  • Receptors, Nicotinic
  • Tropanes
  • nicotinic receptor alpha4beta2
  • pyrido(3,4-b)norhomotropane
  • Nicotine
  • epibatidine