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The Journal of Neuroscience, April 27, 2005, 25(17):4396-4405; doi:10.1523/JNEUROSCI.5269-04.2005
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Cellular/Molecular
A Novel Positive Allosteric Modulator of the  7 Neuronal Nicotinic Acetylcholine Receptor: In Vitro and In Vivo Characterization
Raymond S. Hurst,1
Mihaly Hajós,1
Mario Raggenbass,2
Theron M. Wall,1
Nicole R. Higdon,1
Judy A. Lawson,1
Karen L. Rutherford-Root,1
Mitchell B. Berkenpas,1
W. E. Hoffmann,1
David W. Piotrowski,1
Vincent E. Groppi,1
Geraldine Allaman,2
Roch Ogier,2
Sonia Bertrand,2
Daniel Bertrand,2 and
Stephen P. Arneric1
1Global Research and Development, Pfizer Inc., Groton, Connecticut 06340, and 2Department of Neuroscience, University of Geneva, CH-1211 Geneva 4, Switzerland
Several lines of evidence suggest a link between the  7 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 7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human 7 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 4 2, 34, and 910 nAChRs. PNU-120596 increased the channel mean open time of 7 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 7 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 7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.
Key words: allosteric modulator; nicotinic receptor; 7; hippocampus; auditory gating; PNU-120596
Received Dec 24, 2004;
revised March 10, 2005;
accepted March 28, 2005.
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