Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.
Timmermann DB
,
Sandager-Nielsen K
,
Dyhring T
,
Smith M
,
Jacobsen AM
,
Nielsen EØ
,
Grunnet M
,
Christensen JK
,
Peters D
,
Kohlhaas K
,
Olsen GM
,
Ahring PK
.
???displayArticle.abstract???
Positive allosteric modulation of α4β2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively.Effects of NS9283 were evaluated in vitro using fluorescence-based Ca(2+) imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats.NS9283 was shown to increase agonist-evoked response amplitude of (α4)(3) (β2)(2) nACh receptors in electrophysiology paradigms. (α2)(3) (β2)(2) , (α2)(3) (β4)(2) and (α4)(3) (β4)(2) were modulated to comparable extents, but no effects were detected at α3-containing or any 2α : 3β stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHβE-sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five-choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors.These results provide compelling evidence that positive allosteric modulators acting at the (α4)(3) (β2)(2) nACh receptors can augment activity across a broad range of cognitive domains, and that α4β2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.
Acri,
Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats.
1994, Pubmed
Acri,
Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats.
1994,
Pubmed
Albrecht,
Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators.
2008,
Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed
Bitner,
Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways.
2007,
Pubmed
,
Xenbase
Briggs,
Untranslated region-dependent exclusive expression of high-sensitivity subforms of alpha4beta2 and alpha3beta2 nicotinic acetylcholine receptors.
2006,
Pubmed
,
Xenbase
Cole,
Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions.
1987,
Pubmed
Decker,
Effects of nicotine on spatial memory deficits in rats with septal lesions.
1992,
Pubmed
Dunbar,
Pharmacokinetics and safety profile of ispronicline (TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers.
2006,
Pubmed
Dunbar,
Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI).
2007,
Pubmed
Dunbar,
Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers.
2007,
Pubmed
Faghih,
Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor.
2009,
Pubmed
,
Xenbase
Fenster,
Regulation of alpha4beta2 nicotinic receptor desensitization by calcium and protein kinase C.
1999,
Pubmed
,
Xenbase
Gatto,
TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects.
2004,
Pubmed
Gotti,
Brain nicotinic acetylcholine receptors: native subtypes and their relevance.
2006,
Pubmed
Gotti,
Partial deletion of the nicotinic cholinergic receptor alpha 4 or beta 2 subunit genes changes the acetylcholine sensitivity of receptor-mediated 86Rb+ efflux in cortex and thalamus and alters relative expression of alpha 4 and beta 2 subunits.
2008,
Pubmed
Grottick,
Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands.
2003,
Pubmed
Han,
Localization of nAChR subunit mRNAs in the brain of Macaca mulatta.
2000,
Pubmed
Harpsøe,
Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors.
2011,
Pubmed
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Ji,
Synthesis and structure-activity relationship studies of 3,6-diazabicyclo[3.2.0]heptanes as novel alpha4beta2 nicotinic acetylcholine receptor selective agonists.
2007,
Pubmed
Khiroug,
Rat nicotinic acetylcholine receptor alpha2beta2 channels: comparison of functional properties with alpha4beta2 channels in Xenopus oocytes.
2004,
Pubmed
,
Xenbase
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Lee,
α4β2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of α4β2 nAChR agonists in pain.
2011,
Pubmed
Macdonald,
GABAA receptor channels.
1994,
Pubmed
McGrath,
Guidelines for reporting experiments involving animals: the ARRIVE guidelines.
2010,
Pubmed
Mirza,
Nicotine enhances sustained attention in the rat under specific task conditions.
1998,
Pubmed
Mirza,
NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy.
2008,
Pubmed
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Ng,
Nootropic alpha7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators.
2007,
Pubmed
,
Xenbase
Parikh,
Prefrontal acetylcholine release controls cue detection on multiple timescales.
2007,
Pubmed
Rezvani,
Cognitive effects of nicotine.
2001,
Pubmed
Riekkinen,
Effects of THA and physostigmine on spatial navigation and avoidance performance in mecamylamine and PCPA-treated rats.
1994,
Pubmed
Rowbotham,
A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain.
2009,
Pubmed
Socci,
Nicotine enhances Morris water maze performance of young and aged rats.
1995,
Pubmed
Springer,
Synthesis and activity of substituted carbamates as potentiators of the alpha4beta2 nicotinic acetylcholine receptor.
2008,
Pubmed
Taly,
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
2009,
Pubmed
Timmermann,
An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.
2007,
Pubmed
,
Xenbase
Wada,
Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat.
1989,
Pubmed
,
Xenbase
Weltzin,
Pharmacological characterization of the allosteric modulator desformylflustrabromine and its interaction with alpha4beta2 neuronal nicotinic acetylcholine receptor orthosteric ligands.
2010,
Pubmed
,
Xenbase
Whiteaker,
Pharmacological and immunochemical characterization of alpha2* nicotinic acetylcholine receptors (nAChRs) in mouse brain.
2009,
Pubmed
Yu,
Kinetics of desensitization and recovery from desensitization for human alpha4beta2-nicotinic acetylcholine receptors stably expressed in SH-EP1 cells.
2009,
Pubmed
Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase
Zhu,
Potentiation of analgesic efficacy but not side effects: co-administration of an α4β2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats.
2011,
Pubmed
Zoli,
Developmental regulation of nicotinic ACh receptor subunit mRNAs in the rat central and peripheral nervous systems.
1995,
Pubmed
