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Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders
- Source :
- The Journal of pharmacology and experimental therapeutics. 329(2)
- Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Agonist
Male
Patch-Clamp Techniques
alpha7 Nicotinic Acetylcholine Receptor
medicine.drug_class
Pyridines
Morpholines
Pharmacology
Motor Activity
Receptors, Nicotinic
Neuroprotection
Cell Line
Membrane Potentials
chemistry.chemical_compound
Radioligand Assay
Ganglion type nicotinic receptor
Cognition
medicine
Animals
Humans
Rats, Long-Evans
Nicotinic Agonists
Rats, Wistar
Methyllycaconitine
Behavior, Animal
Molecular Structure
Neurodegenerative Diseases
Rats
Nicotinic agonist
Neuroprotective Agents
chemistry
Molecular Medicine
Cholinergic
Calcium
Alpha-4 beta-2 nicotinic receptor
Cognition Disorders
Acetylcholine
medicine.drug
Protein Binding
Subjects
Details
- ISSN :
- 15210103
- Volume :
- 329
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Accession number :
- edsair.doi.dedup.....edbb0cce09cce33e00f4f1415b25eb68