Department
neurobiology
Document Type
Article
Abstract
Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-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 α3β4-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-5h as possibly superior candidates as aids to smoking cessation. © 2011 American Chemical Society.
Publication Date
3-10-2011
Publication Title
Journal of Medicinal Chemistry
ISSN
00222623
Volume
54
Issue
5
First Page
1441
Last Page
1448
Digital Object Identifier (DOI)
10.1021/jm1014555
Recommended Citation
Carroll, F. Ivy; Muresan, Ana Z.; Blough, Bruce E.; Navarro, Hernan A.; Mascarella, S. Wayne; Eaton, J. Brek; Huang, Xiaodong; Damaj, M. Imad; and Lukas, Ronald J., "Synthesis Of 2-(Substituted Phenyl)-355-Trimethylmorpholine Analogues And Their Effects On Monoamine Uptake Nicotinic Acetylcholine Receptor Function And Behavioral Effects Of Nicotine" (2011). Translational Neuroscience. 281.
https://scholar.barrowneuro.org/neurobiology/281