Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction

J Med Chem. 2009 Nov 12;52(21):6768-81. doi: 10.1021/jm901189z.

Abstract

A series of bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [(3)H]dopamine ([(3)H]DA), [(3)H]serotonin ([(3)H]5HT), and [(3)H]norepinephrine ([(3)H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [(125)I]RTI-55 in cloned transporters. Several analogues showed increased [(3)H]DA uptake inhibition with reduced or little change in [(3)H]5HT and [(3)H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3-chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction.

Publication types

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

MeSH terms

  • Adrenergic Uptake Inhibitors / chemical synthesis
  • Adrenergic Uptake Inhibitors / chemistry
  • Adrenergic Uptake Inhibitors / pharmacology
  • Animals
  • Bupropion / analogs & derivatives*
  • Bupropion / chemical synthesis*
  • Bupropion / pharmacology
  • Cell Line
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / drug therapy*
  • Discrimination Learning / drug effects
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine Uptake Inhibitors / chemical synthesis
  • Dopamine Uptake Inhibitors / chemistry
  • Dopamine Uptake Inhibitors / pharmacology
  • Humans
  • Mice
  • Motor Activity / drug effects
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Radioligand Assay
  • Rats
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Uptake Inhibitors / chemical synthesis
  • Serotonin Uptake Inhibitors / chemistry
  • Serotonin Uptake Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Adrenergic Uptake Inhibitors
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Bupropion
  • Cocaine