Synthesis and Characterization of in Vitro and in Vivo Profiles of Hydroxybupropion Analogues: Aids to Smoking Cessation

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 a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-06, Vol.53 (12), p.4731-4748
Main Authors: Lukas, Ronald J, Muresan, Ana Z, Damaj, M. Imad, Blough, Bruce E, Huang, Xiaodong, Navarro, Hernán A, Mascarella, S. Wayne, Eaton, J. Brek, Marxer-Miller, Syndia K, Carroll, F. Ivy
Format: Article
Language:English
Subjects:
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
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Summary: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 α4β2-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 α4β2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm1003232