Synthesis of 2-(Substituted Phenyl)-3,5,5-trimethylmorpholine Analogues and Their Effects on Monoamine Uptake, Nicotinic Acetylcholine Receptor Function, and Behavioral Effects of Nicotine

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• 作者：F. Ivy Carroll ; Ana Z. Muresan ; Bruce E. Blough ; Herna虂n A. Navarro ; S. Wayne Mascarella ; J. Brek Eaton ; Xiaodong Huang ; M. Imad Damaj ; Ronald J. Lukas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1441-1448
• 全文大小：845K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a鈭?b>5h and their effects on inhibition of dopamine, norepinephrine, and serotonin uptake, nicotinic acetylcholine receptor (nAChR) function, acute actions of nicotine, and nicotine-conditioned place preference (CPP). Several analogues encompassing aryl substitutions, N-alkylation, and alkyl extensions of the morpholine ring 3-methyl group provided analogues more potent in vitro than (S,S)-hydroxybupropion (4a) as inhibitors of dopamine or norepinephrine uptake and antagonists of nAChR function. All of the new (S,S)-5 analogues had better potency than (S,S)-4a as blockers of acute nicotine analgesia in the tail-flick test. Two analogues with highest potency at 伪3尾4*-nAChR and among the most potent transporter inhibitors have better potency than (S,S)-4a in blocking nicotine-CPP. Collectively, these findings illuminate mechanisms of action of 2 analogues and identify deshydroxybupropion analogues 5a鈭?b>5h as possibly superior candidates as aids to smoking cessation.