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

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• 作者：Ronald J. Lukas ; Ana Z. Muresan ; M. Imad Damaj ; Bruce E. Blough ; Xiaodong Huang ; Hernn A. Navarro ; S. Wayne Mascarella ; J. Brek Eaton ; Syndia K. Marxer-Miller ; F. Ivy Carroll
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：June 24, 2010
• 年：2010
• 卷：53
• 期：12
• 页码：4731-4748
• 全文大小：1128K
• 年卷期：v.53,no.12(June 24, 2010)
• ISSN：1520-4804

文摘

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.