To create potentially superior aids to smoking cessation and/or antidepressants and to elucidate bupropions 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 3â€²,4â€²-dichlorophenyl [(Â±)-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 3â€²-fluorophenyl, 3â€²-bromophenyl, and 4-biphenyl analogues 4c, 4d, and 4l, respectively, had higher potency for antagonism of Î±4Î²2-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 Î±4Î²2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence. Â© 2010 American Chemical Society.
Journal of Medicinal Chemistry
Digital Object Identifier (DOI)
Lukas, Ronald J.; Muresan, Ana Z.; Damaj, M. Imad; Blough, Bruce E.; Huang, Xiaodong; Navarro, Hernan A.; Mascarella, S. Wayne; Eaton, J. Brek; Marxer-Miller, Syndia K.; and Carroll, F. Ivy, "Synthesis And Characterization Of In Vitro And In Vivo Profiles Of Hydroxybupropion Analogues: Aids To Smoking Cessation" (2010). Translational Neuroscience. 280.