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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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.

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