A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor: In Vitro and In Vivo Characterization

Autor: Sonia Bertrand, David W. Piotrowski, Vincent E. Groppi, Theron M. Wall, Mario Raggenbass, Raymond S. Hurst, Karen L. Rutherford-Root, Nicole R. Higdon, Mihály Hajós, R. Ogier, William E. Hoffmann, Mitchell B. Berkenpas, Daniel Bertrand, Stephen P. Arneric, Geraldine Allaman, Judy A. Lawson
Jazyk: angličtina
Rok vydání: 2005
Předmět:
Male
Patch-Clamp Techniques
Time Factors
alpha7 Nicotinic Acetylcholine Receptor
Xenopus
Receptors
Nicotinic
Protein Subunits/physiology
Phenylurea Compounds/chemistry/pharmacology
Hippocampus
Cholinergic Antagonists
Membrane Potentials/drug effects/physiology/radiation effects
Membrane Potentials
Rats
Sprague-Dawley
Ganglion type nicotinic receptor
Drug Interactions
Receptor
Amphetamine/pharmacology
Electric Stimulation/methods
Neurons
Acetylcholine/pharmacology
Nicotine/pharmacology
Chemistry
General Neuroscience
Receptors
Nicotinic/ metabolism
Acoustic Stimulation/methods
Nicotinic acetylcholine receptor
Nicotinic agonist
Hippocampus/cytology
Evoked Potentials
Auditory
Alpha-4 beta-2 nicotinic receptor
Evoked Potentials
Auditory/drug effects
Cellular/Molecular
Agonist
Nicotine
Allosteric modulator
Calcium/metabolism
Microinjections
medicine.drug_class
Patch-Clamp Techniques/methods
Tetrodotoxin
Cholinergic Agonists
In Vitro Techniques
complex mixtures
Cell Line
Epithelial Cells/drug effects
Tetrodotoxin/metabolism
Cholinergic Antagonists/pharmacology
Allosteric Regulation
Microinjections/methods
Calcium flux
medicine
Animals
Humans
Neurons/drug effects/physiology
Dose-Response Relationship
Drug
Phenylurea Compounds
Isoxazoles/chemistry/pharmacology
Epithelial Cells
Isoxazoles
Acetylcholine
Electric Stimulation
ddc:616.8
Rats
Cholinergic Agonists/ chemistry/ pharmacology
Amphetamine
Protein Subunits
nervous system
Acoustic Stimulation
Animals
Newborn
Oocytes
Central Nervous System Stimulants/pharmacology
Calcium
Central Nervous System Stimulants
Neuroscience
Zdroj: Journal of Neuroscience, Vol. 25, No 17 (2005) pp. 4396-4405
ISSN: 0270-6474
Popis: Several lines of evidence suggest a link between the alpha7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the alpha7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by alpha4beta2, alpha3beta4, and alpha9alpha10 nAChRs. PNU-120596 increased the channel mean open time of alpha7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of alpha7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances alpha7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.
Databáze: OpenAIRE
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