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1.  Chemistry and Pharmacological Studies of 3-Alkoxy-2,5-Disubstituted-Pyridinyl Compounds as Novel Selective α4β2 Nicotinic Acetylcholine Receptor Ligands That Reduces Alcohol Intake in Rats 
Journal of medicinal chemistry  2013;56(7):10.1021/jm4000374.
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 analogs containing a methyl group at the 2-position of the pyridine ring. In vitro pharmacological studies revealed that some of the novel compounds showed similar overall pharmacological property profiles with that of sazetidine-A, but exhibited reduced agonist activity across all nicotinic receptor subtypes tested. In animal studies, compound (S)-9 significantly reduced alcohol uptake in rats. 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.
doi:10.1021/jm4000374
PMCID: PMC3809750  PMID: 23540678
nicotinic acetylcholine receptors; sazetidine-A; varenicline; desensitization; addiction; alcohol use disorders
2.  Effects of chronic nicotine on heteromeric neuronal nicotinic receptors expressed in rat primary cultured neurons 
Journal of neurochemistry  2011;119(1):153-164.
Nicotine increases the number of neuronal nicotinic receptors (nAChRs) in brain. This study investigated the effects of chronic nicotine treatment on nAChRs expressed in primary cultured neurons. In particular, we studied the chronic effects of nicotine exposure on the total density, surface expression and turnover rate of heteromeric nAChRs. The receptor density was measured by [125I]epibatidine ([125I]EB) binding. Untreated and nicotine-treated neurons were compared from several regions of embryonic (E19) rat brain. Twelve days of treatment with 10 µM nicotine produced a two-fold up-regulation of nAChRs. Biotinylation and whole-cell binding studies indicated that up-regulation resulted from an increase in the number of cell surface receptors as well as intracellular receptors. nAChR subunit composition in cortical and hippocampal neurons was assessed by immunoprecipitation with subunit-selective antibodies. These neurons contain predominantly α4, β2 and α5 subunits, but α2, α3, α6 and β4 subunits were also detected. Chronic nicotine exposure yielded a two-fold increase in the β2-containing receptors and a smaller up-regulation in the α4-containing nAChRs. To explore the mechanisms of up-regulation we investigated the effects of nicotine on the receptor turnover rate. We found that the turnover rate of surface receptors was > two weeks and chronic nicotine exposure had no effect on this rate.
doi:10.1111/j.1471-4159.2011.07408.x
PMCID: PMC3171599  PMID: 21806615
Nicotinic Receptors; Primary neurons; Up-regulation; Cell Surface; Receptor degradation rate
3.  ASSESSING THE EFFECTS OF CHRONIC SAZETIDINE-A DELIVERY ON NICOTINE SELF-ADMINISTRATION IN BOTH MALE AND FEMALE RATS 
Psychopharmacology  2012;222(2):269-276.
Rationale
Sazetidine-A is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined.
Objectives
This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of four weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats.
Methods
Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6 mg/kg/day for four weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-hour sessions over the first two weeks of infusion followed by one week of forced abstinence from nicotine and one week of resumed nicotine access.
Results
The 6 mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p<0.001) and female (p<0.05) rats. The lower 2 mg/kg/day sazetidine-A infusion dose was effective in reducing nicotine self-administration for male (p<0.001), but not female rats. No attenuation in sazetidine-A effectiveness was seen over the course of the four-week treatment. In the vehicle control group, male rats self-administered significantly (p<0.001) more nicotine than females.
Conclusions
The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.
doi:10.1007/s00213-012-2642-z
PMCID: PMC3426624  PMID: 22297831
Nicotine; Sazetidine-A; chronic; Self-administration; Sex differences
4.  Quantitative analysis of the heteromeric neuronal nicotinic receptors in the rat hippocampus 
Journal of neurochemistry  2010;115(3):625-634.
The objective of this study was to identify and quantify the heteromeric neuronal nicotinic receptors (nAChRs) in the rat hippocampus. The density of nAChR subtypes was assessed by labeling them with [3H]epibatidine followed by immunoprecipitation with subunit-selective antibodies. Sequential immunoprecipitation assays were used to establish associations between two different subunits, which then allowed the full subunit composition of the receptors to be deduced. Our results show that most of the hippocampal heteromeric nAChRs contain α4 and β2 subunits. In fact, we identified two populations containing these two predominant subunits, the α4β2 and α4β2α5 subtypes which account for ~40% and ~35%, respectively, of the total [3H]epibatidine-labeled receptors. An additional heteromeric subtype with the subunit composition of α4β2α3 represented ~10% of the total nAChRs, and another 10% of the immunoprecipitated receptors contained α4 and β4 subunits, with or without the α3 subunit. To determine if α4β2 and α4β2α5 nAChR subtypes differ in their ligand binding affinities, the α3- and β4-containing receptors were first removed by immunoprecipitation and then, competition studies with acetylcholine, nicotine, cytisine and sazetidine-A against [3H]epibatidine were carried out on the remaining α4β2 and α4β2α5 subtypes. Results suggested these subtypes have comparable binding affinities for the nicotinic ligands used here.
doi:10.1111/j.1471-4159.2010.06967.x
PMCID: PMC2976603  PMID: 20796176
Neuronal nicotinic receptor; heteromeric subtypes; α5 subunit; hippocampus; immunoprecipitation; binding affinity
5.  The Biology of Tobacco and Nicotine: Bench to Bedside 
Strong epidemiologic evidence links smoking and cancer. An increased understanding of the molecular biology of tobacco-related cancers could advance progress toward improving smoking cessation and patient management. Knowledge gaps between tobacco addiction, tumorigenesis, and cancer brought an interdisciplinary group of investigators together to discuss “The Biology of Nicotine and Tobacco: Bench to Bedside.” Presentations on the signaling pathways and pathogenesis in tobacco-related cancers, mouse models of addiction, imaging and regulation of nicotinic receptors, the genetic basis for tobacco carcinogenesis and development of lung cancer, and molecular mechanisms of carcinogenesis were heard. Importantly, new opportunities to use molecular biology to identify and abrogate tobacco-mediated carcinogenesis and to identify high-risk individuals were recognized.
doi:10.1158/1055-9965.EPI-04-0652
PMCID: PMC3459058  PMID: 15824140
6.  Toxicological Analysis of Low-Nicotine and Nicotine-Free Cigarettes 
Toxicology  2008;249(2-3):194-203.
Low-nicotine and nicotine-free cigarettes are commercially available under the brand-name Quest®. Some consumers may believe that these are safer cigarettes, and they may smoke more cigarettes or inhale more smoke to compensate for low nicotine yields. Thus, we have studied the toxicological effects of these two cigarettes and compared them with the Kentucky reference cigarette 2R4F. Also, the availability of nicotine-free cigarettes allows for the assessing the role of nicotine in cigarette smoke. In addition to nicotine, some tobacco-specific nitrosamines, aldehydes, and volatile organic compounds were also reduced in the Quest® cigarettes compared to the 2R4F. However, aromatic amines were higher in the nicotine-free compared with low nicotine cigarettes. The Ames test revealed that cigarette smoke condensates from the nicotinefree (CSC-F), low nicotine (CSC-L) and 2R4F (CSC-R) cigarettes had a similar mutagenic potency. Exposure to any CSC caused a similar dose-dependent LDH leakage from normal human bronchial epithelial cells. However, CSC-F had more inhibitory effects on the cell growth than CSC-L and CSC-R. Adding nicotine to the CSC-F attenuated this inhibition. Both Quest® CSCs decreased gap junction intercellular communication and caused cell cycle arrest. CSC exposure increased cytoplasmic nucleosomes, sub-G1/G0 population and apoptotic comet tails. Proapoptotic protein Bax increased independent of p53 induction after exposure to CSC-F. In conclusion, these studies are not consistent with a perception that low-nicotine or nicotine-free cigarettes may have less toxicity in human cells. Nicotine, as it exists in CSC, attenuates cytotoxicity possibly in part through inhibition of apoptotic pathways.
doi:10.1016/j.tox.2008.05.009
PMCID: PMC2573966  PMID: 18599178
cigarette smoke; nicotine; mutagenicity; cytotoxicity; apoptosis
7.  Synthesis and Pharmacological Evaluation of Novel 9- and 10- Substituted Cytisine Derivatives - Nicotinic Ligands of Enhanced Subtype Selectivity 
Journal of medicinal chemistry  2006;49(9):2673-2676.
We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the α4β2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
doi:10.1021/jm051196m
PMCID: PMC2504867  PMID: 16640326
8.  Effects of sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats 
Psychopharmacology  2010;211(2):161-174.
Rationale
Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2 nicotinic receptors with only modest receptor activation.
Objectives
The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.
Methods
P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on IV nicotine self-administration in P and NP rats were assessed.
Results
Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.
Conclusions
Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.
doi:10.1007/s00213-010-1878-8
PMCID: PMC3695635  PMID: 20535453
Alcoholism; P rats; Nicotinic agonists; Alcohol drinking; Naltrexone; Treatment; Animal model; Saccharin; Nicotine addiction

Results 1-8 (8)