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    Lecozotan (SRA-333): a selective serotonin1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.

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    Publication date
    2005
    Author
    Harder, Josie A.
    Womack, Matthew D.
    Schechter, L.E.
    Smith, D.L.
    Childers, W.
    Rosenzweig-Lipson, S.
    Sukoff, S.
    Keyword
    5-HT1A
    5-HT1A receptor
    Alzheimer's Disease
    Cognition
    Lecozotan
    Serotonin antagonist
    Peer-Reviewed
    Yes
    
    Metadata
    Show full item record
    Abstract
    Recent data has suggested that the 5-HT1A receptor is involved in cognitive processing. A novel 5- HT1A receptor antagonist, 4-cyano-N- [(2R)-[4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) piperazin-1-yl] propyl]-N-pyridin-2-yl-benzamide hydrochloride (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacologic assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT1A receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg sc) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg sc) of 8 OH-DPAT and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT1A receptor tolerance or desensitization in a behavioral model indicative of 5- HT1A receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg im) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT1A agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg po). Learning deficits induced by the glutamatergic antagonist MK-801 (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg im) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in AD.
    URI
    http://hdl.handle.net/10454/3679
    Version
    No full-text available in the repository
    Citation
    Harder, J.A., Womack, M., Schechter, M.E. and Smith, D.L. et al. (2005). Lecozotan (SRA-333): a selective serotonin1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties. Journal of Pharmacology and Experimental Therapeutics. Vol. 314, No. 3, pp. 1274-1289.
    Link to publisher’s version
    http://dx.doi.org/10.1124/jpet.105.086363
    Type
    Article
    Collections
    Life Sciences Publications

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