The discovery of an unusually selective and novel cocaine analog: difluoropine. Synthesis and inhibition of binding at cocaine recognition sites

J Med Chem. 1994 Jun 24;37(13):2001-10. doi: 10.1021/jm00039a014.

Abstract

Cocaine is a stimulant drug with a high abuse liability. Although it inhibits several monamine transporters in the mammalian brain, its primary mechanism of action has been ascribed to its inhibition of the dopamine transporter. The synthesis, characterization, and receptor binding properties of all eight isomers of a unique tropane analog, 2-carbomethoxy-3-[bis(4-fluorophenyl)-methoxy]tropane is described. In addition, we report that the S-enantiomer, (S)-(+)-2 beta- carbomethoxy-3 alpha-[bis(4-fluorophenyl)methoxy]tropane, Difluoropine, is a potent (IC50 10.9 nM) and selective (324 [DA/5HT]) ligand for the dopamine transporter.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Brain / metabolism
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Chromatography, High Pressure Liquid
  • Cocaine / analogs & derivatives*
  • Cocaine / chemical synthesis
  • Cocaine / chemistry
  • Cocaine / metabolism
  • Cocaine / pharmacology
  • Dopamine Plasma Membrane Transport Proteins
  • Dose-Response Relationship, Drug
  • Macaca fascicularis
  • Magnetic Resonance Spectroscopy
  • Membrane Glycoproteins*
  • Membrane Transport Proteins*
  • Nerve Tissue Proteins*
  • Receptors, Dopamine / drug effects*
  • Receptors, Dopamine / metabolism
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Stereoisomerism

Substances

  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, Dopamine
  • Receptors, Serotonin
  • difluoropine
  • Cocaine