Synthesis and nicotinic binding studies on enantiopure pinnamine variants with an 8-azabicyclo[3.2.1]octane moiety

Pharmazie. 2003 May;58(5):295-9.

Abstract

Bioisosteric replacement of the 9-azabicyclo[4.2.1]nonane pharmacophoric element of the novel alkaloidal marine toxine pinnamine (5) by the 8-azabicyclo[3.2.1]octane moiety resulted in conformationally restricted analogues 6a and 6c of (-)-ferruginine (4). Key step in the diastereoselective synthesis of these pyranotropanes was the condensation of enantiopure ecgonine methyl ester (9) from the "chiral pool" with the lithium anion of N-tert-butylbutyraldimin and subsequent cyclisation with TFA. The potential nAChR ligands were tested for their in vitro affinity for the (alpha4)2(beta2)3 and the alpha7* nAChR subtypes. Despite obvious structural similarities with the potent alkaloids pinnamine (5) and (-)-ferruginine (4) the pyranotropanes 6a and 6c exhibited distinctly lower nAChR affinities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Cyclooctanes / chemical synthesis*
  • Cyclooctanes / pharmacology
  • Drug Design
  • In Vitro Techniques
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Nicotinic / drug effects*
  • Spectrophotometry, Infrared
  • Spectroscopy, Fourier Transform Infrared
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 8-azabicyclo(3.2.1)octane
  • Aza Compounds
  • Cyclooctanes
  • Indicators and Reagents
  • Receptors, Nicotinic