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Acta Pharmacol Sin
2019 Jun 01;406:737-745. doi: 10.1038/s41401-018-0163-y.
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Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.
Sun LL
,
Yang TY
,
Wei NN
,
Lu W
,
Jiao WX
,
Zhou QQ
,
Miao YZ
,
Gao Q
,
Wang XT
,
Sun Q
,
Wang K
.
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The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1β3γ2 and α5β3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type IPAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer''s disease.
Alkondon,
Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices.
1997, Pubmed
Alkondon,
Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices.
1997,
Pubmed
Bristow,
The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia.
2016,
Pubmed
Buhler,
alpha7 nicotinic acetylcholine receptors on GABAergic interneurons evoke dendritic and somatic inhibition of hippocampal neurons.
2002,
Pubmed
Callahan,
Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates.
2013,
Pubmed
Callahan,
Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats.
2014,
Pubmed
Corradi,
Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery.
2016,
Pubmed
Cui,
Tropisetron attenuates naloxone-induced place aversion in single-dose morphine-treated rats: role of alpha7 nicotinic receptors.
2009,
Pubmed
Dineley,
Nicotinic ACh receptors as therapeutic targets in CNS disorders.
2015,
Pubmed
Elvevåg,
Cognitive impairment in schizophrenia is the core of the disorder.
2000,
Pubmed
Felix,
Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats.
1997,
Pubmed
Freedman,
α7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia.
2014,
Pubmed
Freedman,
Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia.
1995,
Pubmed
Freedman,
Initial phase 2 trial of a nicotinic agonist in schizophrenia.
2008,
Pubmed
Freedman,
Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.
1997,
Pubmed
Gee,
First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288.
2017,
Pubmed
Gotti,
Brain nicotinic acetylcholine receptors: native subtypes and their relevance.
2006,
Pubmed
Guan,
Two-electrode voltage clamp.
2013,
Pubmed
Hajós,
The selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats.
2005,
Pubmed
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
Ji,
Inhibition and disinhibition of pyramidal neurons by activation of nicotinic receptors on hippocampal interneurons.
2000,
Pubmed
Kaech,
Culturing hippocampal neurons.
2006,
Pubmed
Leiser,
A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits.
2009,
Pubmed
Liang,
Structural Insights into KChIP4a Modulation of Kv4.3 Inactivation.
2009,
Pubmed
Martin,
Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.
2004,
Pubmed
Martin,
Schizophrenia and the alpha7 nicotinic acetylcholine receptor.
2007,
Pubmed
McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed
Ng,
Nootropic alpha7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators.
2007,
Pubmed
Nikiforuk,
Positive allosteric modulation of alpha 7 nicotinic acetylcholine receptors enhances recognition memory and cognitive flexibility in rats.
2015,
Pubmed
Nikiforuk,
Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats.
2016,
Pubmed
O'Neill,
DMXB, an alpha7 nicotinic agonist, normalizes auditory gating in isolation-reared rats.
2003,
Pubmed
Ochoa,
Cognitive deficits in schizophrenia: focus on neuronal nicotinic acetylcholine receptors and smoking.
2007,
Pubmed
Olincy,
Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.
2006,
Pubmed
Potasiewicz,
3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats.
2017,
Pubmed
Radcliffe,
Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal neurons.
1999,
Pubmed
Simosky,
Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice.
2001,
Pubmed
Stevens,
Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains.
1996,
Pubmed
Stevens,
Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice.
1998,
Pubmed
Stevens,
Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models.
1997,
Pubmed
Taly,
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
2009,
Pubmed
Tamminga,
Phenotype of schizophrenia: a review and formulation.
2005,
Pubmed
Tang,
Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B.
2015,
Pubmed
Townsend,
α7-nAChR agonist enhances neural plasticity in the hippocampus via a GABAergic circuit.
2016,
Pubmed
Wallace,
Alpha7 neuronal nicotinic receptors as a drug target in schizophrenia.
2013,
Pubmed
Wallace,
RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents.
2011,
Pubmed
Wallace,
Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease.
2011,
Pubmed
Wonnacott,
Presynaptic nicotinic ACh receptors.
1997,
Pubmed
Yang,
The current agonists and positive allosteric modulators of α7 nAChR for CNS indications in clinical trials.
2017,
Pubmed
Young,
Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice.
2007,
Pubmed
de Fiebre,
Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.
1995,
Pubmed
