title: 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.
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.
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, North Carolina 27709-2194, United States. fic@rti.org
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: Ana Z
authors.initials: AZ
authors.lastname: Muresan
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Huang
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism*; D001831:Body Temperature / Q000187:drug effects; D016642:Bupropion / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D016540:Smoking Cessation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015306:Biogenic Monoamines; D018765:Dopamine Uptake Inhibitors; D009025:Morpholines; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D016642:Bupropion; D012701:Serotonin; D009538:Nicotine; C496215:radafaxine; D004298:Dopamine; D009638:Norepinephrine