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,35)-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 alpha 4 beta 2-nAChR than (2S,3S)-4a. Several analogues also had higher potency than (2S,35)-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 alpha 4 beta 2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence.
Lukas, R. J., Muresan, A. Z., Damaj, M. I., Blough, B., Huang, X. D., Navarro, H., ... Carroll, F. (2010). Synthesis and Characterization of in Vitro and in Vivo Profiles of Hydroxybupropion Analogues: Aids to Smoking Cessation. Journal of Medicinal Chemistry, 53(12), 4731-4748.