ArticleBritish journal of pharmacology2013
Unravelling the mechanism of action of NS9283, a positive allosteric modulator of (α4)3(β2)2 nicotinic ACh receptors.
Article in British journal of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Targeted Mutations Activate Allosteric Modulation of α5-Containing Nicotinic Acetylcholine Receptors.ACS chemical neuroscience · 2026Article
- A Pharmacophore for Drugs Targeting the α4α4 Binding Site of the (α4)Journal of neurochemistry · 2025Article
- SR9883 is a novel small-molecule enhancer of α4β2* nicotinic acetylcholine receptor signaling that decreases intravenous nicotine self-administration in rats.Frontiers in molecular neuroscience · 2024Article
- Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors.Molecules (Basel, Switzerland) · 2022Article
- Article
- More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder.Pharmacological reviews · 2020Review
- Potentiation of a neuronal nicotinic receptor via pseudo-agonist site.Cellular and molecular life sciences : CMLS · 2019Article
- Stoichiometry of the Heteromeric Nicotinic Receptors of the Renshaw Cell.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Attenuation of nicotine taking and seeking in rats by the stoichiometry-selective alpha4beta2 nicotinic acetylcholine receptor positive allosteric modulator NS9283.Psychopharmacology · 2017Article
- Article
- An Accessory Agonist Binding Site Promotes Activation of α4β2* Nicotinic Acetylcholine Receptors.The Journal of biological chemistry · 2015Article
- Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors.The Journal of biological chemistry · 2014Article
- Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors.ACS chemical biology · 2014Article
- Synthesis and activity of substituted heteroaromatics as positive allosteric modulators for α4β2α5 nicotinic acetylcholine receptors.Bioorganic & medicinal chemistry letters · 2014Article
- Two distinct allosteric binding sites at α4β2 nicotinic acetylcholine receptors revealed by NS206 and NS9283 give unique insights to binding activity-associated linkage at Cys-loop receptors.The Journal of biological chemistry · 2013Article
- Selective potentiation of (α4)3(β2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats.Biochemical pharmacology · 2013Article
- Neuronal nicotinic receptors as analgesic targets: it's a winding road.Biochemical pharmacology · 2013Review
- Nicotinic modulation of intrinsic brain networks in schizophrenia.Biochemical pharmacology · 2013Review
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5 authors.
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No grant is acknowledged in the PubMed record.
Abstract
background and purposeStrong implications in major neurological diseases make the neuronal α4β2 nicotinic ACh receptor (nAChR) a highly interesting drug target. In this study, we present a detailed electrophysiological characterization of NS9283, a potent positive allosteric modulator acting selectively at 3α:2β stoichiometry of α2* and α4* nAChRs. EXPERIMENTAL APPROACH: The whole-cell patch-clamp technique equipped with an ultra-fast drug application system was used to perform electrophysiological characterization of NS9283 modulatory actions on human α4β2 nAChRs stably expressed in HEK293 cells (HEK293-hα4β2). KEY
resultsNS9283 was demonstrated to increase the potency of ACh-evoked currents in HEK293-hα4β2 cells by left-shifting the concentration-response curve ~60-fold. Interestingly, this modulation did not significantly alter maximal efficacy levels of ACh. Further, NS9283 did not affect the rate of desensitization of ACh-evoked currents, was incapable of reactivating desensitized receptors and only moderately slowed recovery from desensitization. However, NS9283 strongly decreased the rate of deactivation kinetics and also modestly decreased the rate of activation. This resulted in a left-shift of the ACh window current of (α4)3(β2)2 nAChRs in the presence of NS9283. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that NS9283 increases responsiveness of human (α4)3(β2)2 nAChR to ACh with no change in maximum efficacy. We propose that this potentiation is due to a significant slowing of deactivation kinetics. In summary, the mechanism of action of NS9283 bears high resemblance to that of benzodiazepines at the GABAA receptor and to our knowledge, NS9283 constitutes the first nAChR compound of this class.
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