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Nicotine Tob Res
2015 Mar 01;173:361-7. doi: 10.1093/ntr/ntu170.
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Functional characterization of AT-1001, an α3β4 nicotinic acetylcholine receptor ligand, at human α3β4 and α4β2 nAChR.
Zaveri NT
,
Bertrand S
,
Yasuda D
,
Bertrand D
.
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INTRODUCTION: Genome-wide association studies linking the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits to nicotine dependence suggest that α3β4* nAChR may be targets for smoking cessation pharmacotherapies. We previously reported that AT-1001, a selective α3β4* nAChR ligand binds with high affinity to rat α3β4 and human α3β4α5 nAChR, antagonizes epibatidine-induced activation of rat α3β4 nAChR in HEK cells and potently inhibits nicotine self-administration in rats.
METHODS: Two-electrode voltage clamp was used for functional characterization of AT-1001 at recombinant human α3β4 and α4β2 nAChR expressed in Xenopus oocytes.
RESULTS: Concentration-response curves show that AT-1001 is a partial agonist at human α3β4 nAChR, evoking up to 35% of the maximal acetylcholine (ACh) response (50% effective concentration [EC50] = 0.37 μM). AT-1001 showed very little agonist activity at the α4β2 nAChR, evoking only 6% of the ACh response (EC50 = 1.5 μM). Pre- and co-application of various concentrations of AT-1001 with 50 μM ACh revealed a complex pattern of activation-inhibition by AT-1001 at α3β4 nAChR, which was best fitted by a 2-site equation. At α4β2 nAChR, co-exposure of AT-1001 with ACh only showed inhibition of ACh current with a shallower curve.
CONCLUSIONS: AT-1001 is a partial agonist at the human α3β4 nAChR and causes desensitization at concentrations at which it evokes an inward current, resulting in an overall functional antagonism of α3β4 nAChR. AT-1001 does not significantly activate or desensitize α4β2 nAChR at the same concentrations as at the α3β4 nAChR, but does inhibit ACh responses at α4β2 nAChR at higher concentrations. A combination of these mechanisms may underlie the inhibition of nicotine self-administration by AT-1001, suggesting that AT-1001 and compounds from this class may have clinical potential for smoking cessation pharmacotherapy.
Berrettini,
Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking.
2008, Pubmed
Berrettini,
Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking.
2008,
Pubmed
Buisson,
The unusual nature of epibatidine responses at the alpha4beta2 nicotinic acetylcholine receptor.
2000,
Pubmed
Cachelin,
Unusual pharmacology of (+)-tubocurarine with rat neuronal nicotinic acetylcholine receptors containing beta 4 subunits.
1994,
Pubmed
,
Xenbase
Caporaso,
Genome-wide and candidate gene association study of cigarette smoking behaviors.
2009,
Pubmed
Corrigall,
The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine.
1992,
Pubmed
Fowler,
Habenular α5 nicotinic receptor subunit signalling controls nicotine intake.
2011,
Pubmed
Frahm,
Aversion to nicotine is regulated by the balanced activity of β4 and α5 nicotinic receptor subunits in the medial habenula.
2011,
Pubmed
,
Xenbase
Gallego,
Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects.
2012,
Pubmed
Grady,
Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the alpha3beta4* and alpha3beta3beta4* subtypes mediate acetylcholine release.
2009,
Pubmed
Graupner,
Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine.
2013,
Pubmed
Görlich,
Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons.
2013,
Pubmed
Hogg,
An automated system for intracellular and intranuclear injection.
2008,
Pubmed
,
Xenbase
Maskos,
Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.
2005,
Pubmed
McCallum,
Differential regulation of mesolimbic alpha 3/alpha 6 beta 2 and alpha 4 beta 2 nicotinic acetylcholine receptor sites and function after long-term oral nicotine to monkeys.
2006,
Pubmed
Picciotto,
Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.
1998,
Pubmed
Rollema,
Pre-clinical properties of the alpha4beta2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence.
2010,
Pubmed
,
Xenbase
Rollema,
Functional interactions of varenicline and nicotine with nAChR subtypes implicated in cardiovascular control.
2014,
Pubmed
,
Xenbase
Saccone,
The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans.
2009,
Pubmed
Salas,
Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit.
2004,
Pubmed
Schlaepfer,
The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults.
2008,
Pubmed
Smulders,
Cholinergic drugs potentiate human nicotinic alpha4beta2 acetylcholine receptors by a competitive mechanism.
2005,
Pubmed
,
Xenbase
Stoker,
Role of α7- and β4-containing nicotinic acetylcholine receptors in the affective and somatic aspects of nicotine withdrawal: studies in knockout mice.
2012,
Pubmed
Tapper,
Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization.
2004,
Pubmed
Toll,
AT-1001: a high affinity and selective α3β4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats.
2012,
Pubmed
Weiss,
A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction.
2008,
Pubmed
Wu,
[¹²⁵I]AT-1012, a new high affinity radioligand for the α3β4 nicotinic acetylcholine receptors.
2014,
Pubmed
Zaveri,
Novel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation.
2010,
Pubmed
Zwart,
Competitive potentiation of acetylcholine effects on neuronal nicotinic receptors by acetylcholinesterase-inhibiting drugs.
2000,
Pubmed
,
Xenbase