Source:http://linkedlifedata.com/resource/pubmed/id/19223665
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
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| pubmed:dateCreated |
2009-4-24
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| pubmed:abstractText |
The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholines,
http://linkedlifedata.com/resource/pubmed/chemical/Neuroprotective Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Nicotinic Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Nicotinic,
http://linkedlifedata.com/resource/pubmed/chemical/alpha7 nicotinic acetylcholine...
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| pubmed:status |
MEDLINE
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| pubmed:month |
May
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| pubmed:issn |
1521-0103
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| pubmed:author |
pubmed-author:AschmiSuzanS,
pubmed-author:BothmannHendrickH,
pubmed-author:ComeryThomas ATA,
pubmed-author:DunlopJohnJ,
pubmed-author:GhironChiaraC,
pubmed-author:GianfriddoMarcoM,
pubmed-author:GrauerSteven MSM,
pubmed-author:HaydarSimonS,
pubmed-author:JowBrianB,
pubmed-author:KelleyCodyC,
pubmed-author:KowalDianneD,
pubmed-author:RoncaratiRenzaR,
pubmed-author:ScaliCarlaC,
pubmed-author:TerstappenGeorg CGC,
pubmed-author:ZanelliUgoU
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| pubmed:issnType |
Electronic
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| pubmed:volume |
329
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
459-68
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| pubmed:dateRevised |
2010-6-4
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| pubmed:meshHeading |
pubmed-meshheading:19223665-Animals,
pubmed-meshheading:19223665-Behavior, Animal,
pubmed-meshheading:19223665-Calcium,
pubmed-meshheading:19223665-Cell Line,
pubmed-meshheading:19223665-Cognition,
pubmed-meshheading:19223665-Cognition Disorders,
pubmed-meshheading:19223665-Humans,
pubmed-meshheading:19223665-Male,
pubmed-meshheading:19223665-Membrane Potentials,
pubmed-meshheading:19223665-Molecular Structure,
pubmed-meshheading:19223665-Morpholines,
pubmed-meshheading:19223665-Motor Activity,
pubmed-meshheading:19223665-Neurodegenerative Diseases,
pubmed-meshheading:19223665-Neuroprotective Agents,
pubmed-meshheading:19223665-Nicotinic Agonists,
pubmed-meshheading:19223665-Patch-Clamp Techniques,
pubmed-meshheading:19223665-Protein Binding,
pubmed-meshheading:19223665-Pyridines,
pubmed-meshheading:19223665-Radioligand Assay,
pubmed-meshheading:19223665-Rats,
pubmed-meshheading:19223665-Rats, Long-Evans,
pubmed-meshheading:19223665-Rats, Wistar,
pubmed-meshheading:19223665-Receptors, Nicotinic
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| pubmed:year |
2009
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| pubmed:articleTitle |
Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders.
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| pubmed:affiliation |
Siena Biotech SpA, Siena, Italy. rroncarati@sienabiotech.it
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| pubmed:publicationType |
Journal Article
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