Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation

J Med Chem. 2010 Jun 24;53(12):4731-48. doi: 10.1021/jm1003232.

Abstract

To create potentially superior aids to smoking cessation and/or antidepressants and to elucidate bupropion's possible mechanisms of action(s), 23 analogues based on its active hydroxymetabolite (2S,3S)-4a were synthesized and tested for their abilities to inhibit monoamine uptake and nAChR subtype activities in vitro and acute effects of nicotine in vivo. The 3',4'-dichlorophenyl [(+/-)-4n], naphthyl (4r), and 3-chlorophenyl or 3-propyl analogues 4s and 4t, respectively, had higher inhibitory potency and/or absolute selectivity than (2S,3S)-4a for inhibition of DA, NE, or 5HT uptake. The 3'-fluorophenyl, 3'-bromophenyl, and 4-biphenyl analogues 4c, 4d, and 4l, respectively, had higher potency for antagonism of alpha4beta2-nAChR than (2S,3S)-4a. Several analogues also had higher potency than (2S,3S)-4a as antagonists of nicotine-mediated antinociception in the tail-flick assay. The results suggest that compounds acting via some combination of DA, NE, or 5HT inhibition and/or antagonism of alpha4beta2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence.

Publication types

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

MeSH terms

  • Adrenergic Uptake Inhibitors / chemical synthesis*
  • Adrenergic Uptake Inhibitors / chemistry
  • Adrenergic Uptake Inhibitors / pharmacology
  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Body Temperature / drug effects
  • Bupropion / analogs & derivatives*
  • Bupropion / chemical synthesis
  • Bupropion / chemistry
  • Bupropion / pharmacology
  • Cell Line
  • Dopamine Uptake Inhibitors / chemical synthesis*
  • Dopamine Uptake Inhibitors / chemistry
  • Dopamine Uptake Inhibitors / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Motor Activity / drug effects
  • Nicotine / pharmacology
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / chemical synthesis*
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology
  • Receptors, Nicotinic / physiology
  • Serotonin Uptake Inhibitors / chemical synthesis*
  • Serotonin Uptake Inhibitors / chemistry
  • Serotonin Uptake Inhibitors / pharmacology
  • Smoking Cessation
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adrenergic Uptake Inhibitors
  • Analgesics
  • Dopamine Uptake Inhibitors
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • Serotonin Uptake Inhibitors
  • nicotinic receptor alpha4beta2
  • Bupropion
  • Nicotine
  • radafaxine