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Nicotine Tob Res
2019 May 21;216:805-812. doi: 10.1093/ntr/ntx187.
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Cracking the Betel Nut: Cholinergic Activity of Areca Alkaloids and Related Compounds.
Horenstein NA
,
Quadri M
,
Stokes C
,
Shoaib M
,
Papke RL
.
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INTRODUCTION: The use of betel quid is the most understudied major addiction in the world. The neuropsychological activity of betel quid has been attributed to alkaloids of Areca catechu. With the goal of developing novel addiction treatments, we evaluate the muscarinic and nicotinic activity of the four major Areca alkaloids: arecoline, arecaidine, guvacoline, and guvacine and four structurally related compounds.
METHODS: Acetylcholine receptors were expressed in Xenopus oocytes and studied with two-electrode voltage clamp.
RESULTS: Both arecoline- and guvacoline-activated muscarinic acetylcholine receptors (mAChR), while only arecoline produced significant activation of nicotinic AChR (nAChR). We characterized four additional arecoline-related compounds, seeking an analog that would retain selective activity for a α4* nAChR, with diminished effects on mAChR and not be a desensitizer of α7 nAChR. We show that this profile is largely met by isoarecolone. Three additional arecoline analogs were characterized. While the quaternary dimethyl analog had a broad range of activities, including activation of mAChR and muscle-type nAChR, the methyl analog only activated a range of α4* nAChR, albeit with low potency. The ethyl analog had no detectable cholinergic activity.
CONCLUSIONS: Evidence indicates that α4* nAChR are at the root of nicotine addiction, and this may also be the case for betel addiction. Our characterization of isoarecolone and 1-(4-methylpiperazin-1-yl) ethanone as truly selective α4*nAChR selective partial agonists with low muscarinic activity may point toward a promising new direction for the development of drugs to treat both nicotine and betel addiction.
IMPLICATIONS: Nearly 600 million people use Areca nut, often with tobacco. Two of the Areca alkaloids are muscarinic acetylcholine receptor agonists, and one, arecoline, is a partial agonist for the α4* nicotinic acetylcholine receptors (nAChR) associated with tobacco addiction. The profile of arecoline activity suggested its potential to be used as a scaffold for developing new tobacco cessation drugs if analogs can be identified that retain the same nicotinic receptor selectivity without muscarinic activity. We report that isoarecolone is a selective partial agonist for α4* nAChR with minimal muscarinic activity and 1-(4-methylpiperazin-1-yl) ethanone has similar nAChR selectivity and no detectable muscarinic action.
Akhtar,
Areca nut chewing and esophageal squamous-cell carcinoma risk in Asians: a meta-analysis of case-control studies.
2013, Pubmed
Akhtar,
Areca nut chewing and esophageal squamous-cell carcinoma risk in Asians: a meta-analysis of case-control studies.
2013,
Pubmed
Andersen,
Synthesis of novel gamma-aminobutyric acid (GABA) uptake inhibitors. 5.(1) Preparation and structure-activity studies of tricyclic analogues of known GABA uptake inhibitors.
2001,
Pubmed
Brunzell,
Diverse strategies targeting α7 homomeric and α6β2* heteromeric nicotinic acetylcholine receptors for smoking cessation.
2014,
Pubmed
Buccafusco,
Isoarecolone-induced enhancement of delayed matching to sample performance in monkeys: role of nicotinic receptors.
1995,
Pubmed
Buckley,
Localization of a family of muscarinic receptor mRNAs in rat brain.
1988,
Pubmed
Cahill,
Nicotine receptor partial agonists for smoking cessation.
2007,
Pubmed
Campling,
Acute activation, desensitization and smoldering activation of human acetylcholine receptors.
2013,
Pubmed
Chu,
Neurological aspects of areca and betel chewing.
2002,
Pubmed
Franke,
University of Hawai'i Cancer Center connection: Areca (betel) nut consumption: an underappreciated cause of cancer.
2014,
Pubmed
Garcha,
Behavioural and ligand-binding studies in rats with 1-acetyl-4-methylpiperazine, a novel nicotinic agonist.
1993,
Pubmed
Gotti,
Heterogeneity and complexity of native brain nicotinic receptors.
2007,
Pubmed
Hahn,
Attentional effects of nicotinic agonists in rats.
2003,
Pubmed
Hasselmo,
The role of acetylcholine in learning and memory.
2006,
Pubmed
Herzog,
The Betel Quid Dependence Scale: replication and extension in a Guamanian sample.
2014,
Pubmed
Horenstein,
Multiple pharmacophores for the selective activation of nicotinic alpha7-type acetylcholine receptors.
2008,
Pubmed
,
Xenbase
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Kao,
An overview of detection and screening of oral cancer in Taiwan.
2015,
Pubmed
Koob,
Plasticity of reward neurocircuitry and the 'dark side' of drug addiction.
2005,
Pubmed
Kuryatov,
Expression of functional human α6β2β3* acetylcholine receptors in Xenopus laevis oocytes achieved through subunit chimeras and concatamers.
2011,
Pubmed
,
Xenbase
Lee,
Population burden of betel quid abuse and its relation to oral premalignant disorders in South, Southeast, and East Asia: an Asian Betel-quid Consortium Study.
2012,
Pubmed
Lee,
Betel-quid dependence domains and syndrome associated with betel-quid ingredients among chewers: an Asian multi-country evidence.
2014,
Pubmed
Liu,
The pharmacology, toxicology and potential applications of arecoline: a review.
2016,
Pubmed
Lord,
Chemical and analytical aspects of areca nut.
2002,
Pubmed
Lummis,
Varenicline is a potent agonist of the human 5-hydroxytryptamine3 receptor.
2011,
Pubmed
,
Xenbase
Manetti,
Hybridized and isosteric analogues of N1-acetyl-N4-dimethyl-piperazinium iodide (ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (DMPP) with central nicotinic action.
1999,
Pubmed
Mihalak,
Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors.
2006,
Pubmed
,
Xenbase
Miledi,
Oscillatory chloride current evoked by temperature jumps during muscarinic and serotonergic activation in Xenopus oocyte.
1987,
Pubmed
,
Xenbase
Miledi,
A calcium-dependent transient outward current in Xenopus laevis oocytes.
1982,
Pubmed
,
Xenbase
Mirza,
The nicotinic receptor agonists (-)-nicotine and isoarecolone differ in their effects on dopamine release in the nucleus accumbens.
1996,
Pubmed
Morales-Perez,
X-ray structure of the human α4β2 nicotinic receptor.
2016,
Pubmed
Moser,
Structure-activity relationships of new analogues of arecaidine propargyl ester at muscarinic M1 and M2 receptor subtypes.
1989,
Pubmed
Papke,
An evaluation of neuronal nicotinic acetylcholine receptor activation by quaternary nitrogen compounds indicates that choline is selective for the alpha 7 subtype.
1996,
Pubmed
,
Xenbase
Papke,
Similar activity of mecamylamine stereoisomers in vitro and in vivo.
2013,
Pubmed
,
Xenbase
Papke,
Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.
2011,
Pubmed
,
Xenbase
Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase
Papke,
The pharmacological activity of nicotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery.
2007,
Pubmed
,
Xenbase
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Papke,
Merging old and new perspectives on nicotinic acetylcholine receptors.
2014,
Pubmed
Papke,
Activation and inhibition of mouse muscle and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
2010,
Pubmed
,
Xenbase
Papke,
The minimal pharmacophore for silent agonism of the α7 nicotinic acetylcholine receptor.
2014,
Pubmed
,
Xenbase
Papke,
Nicotinic Activity of Arecoline, the Psychoactive Element of "Betel Nuts", Suggests a Basis for Habitual Use and Anti-Inflammatory Activity.
2015,
Pubmed
,
Xenbase
Peng,
Areca catechu L. (Arecaceae): a review of its traditional uses, botany, phytochemistry, pharmacology and toxicology.
2015,
Pubmed
Picciotto,
Molecular mechanisms underlying behaviors related to nicotine addiction.
2013,
Pubmed
Pons,
Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration.
2008,
Pubmed
Reavill,
Isoarecolone can inhibit nicotine binding and produce nicotine-like discriminative stimulus effects in rats.
1987,
Pubmed
Reavill,
Locomotor activity in rats after administration of nicotinic agonists intracerebrally.
1990,
Pubmed
Shoaib,
Effects of isoarecolone, a nicotinic receptor agonist in rodent models of nicotine dependence.
2006,
Pubmed
Song,
Betel quid chewing without tobacco: a meta-analysis of carcinogenic and precarcinogenic effects.
2015,
Pubmed
Whiteaker,
Locomotor activation and dopamine release produced by nicotine and isoarecolone in rats.
1995,
Pubmed
Winstock,
A dependency syndrome related to areca nut use: some medical and psychological aspects among areca nut users in the Gujarat community in the UK.
2000,
Pubmed
Wolf-Pflugmann,
Synthesis and muscarinic activity of a series of tertiary and quaternary N-substituted guvacine esters structurally related to arecoline and arecaidine propargyl ester.
1989,
Pubmed
Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase
