title: Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective α4β2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats.
abstract: Neuronal acetylcholine receptors mediate the addictive effects of nicotine and may also be involved in alcohol addiction. Varenicline, an approved smoking cessation medication, showed clear efficacy in reducing alcohol consumption in heavy-drinking smokers. More recently, sazetidine-A, which selectively desensitizes α4β2 nicotinic receptors, was shown to significantly reduce alcohol intake in a rat model. To develop novel therapeutics for treating alcohol use disorder, we designed and synthesized novel sazetidine-A analogues containing a methyl group at the 2-position of the pyridine ring. In vitro pharmacological studies revealed that some of the novel compounds showed overall pharmacological property profiles similar to that of sazetidine-A but exhibited reduced agonist activity across all nicotinic receptor subtypes tested. In rat studies, compound (S)-9 significantly reduced alcohol uptake. More importantly, preliminary results from studies in a ferret model indicate that these novel nAChR ligands have an improved adverse side-effect profile in comparison with that of varenicline.
authors.affiliation: Center for Drug Discovery, Georgetown University Medical Center , Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Janell
authors.initials: J
authors.lastname: Richardson
authors.forename: Thao
authors.initials: T
authors.lastname: Tran
authors.forename: Nour
authors.initials: N
authors.lastname: Al-Muhtasib
authors.forename: Teresa
authors.initials: T
authors.lastname: Xie
authors.forename: Venkata Mahidhar
authors.initials: VM
authors.lastname: Yenugonda
authors.forename: Hannah G
authors.initials: HG
authors.lastname: Sexton
authors.forename: Amir H
authors.initials: AH
authors.lastname: Rezvani
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: Niaz
authors.initials: N
authors.lastname: Sahibzada
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kellar
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
mesh_terms: D000428:Alcohol Drinking / Q000517:prevention & control*; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage*; D005289:Ferrets; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D000431:Ethanol
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