| Autor: |
Chambers, M. S., Atack, J. R., Broughton, H. B., Collinson, N., Cook, S., Dawson, G. R., Hobbs, S. C., Marshall, G., Maubach, K. A., Pillai, G. V., Reeve, A. J., MacLeod, A. M. |
| Zdroj: |
Journal of Medicinal Chemistry; May 2003, Vol. 46 Issue: 11 p2227-2240, 14p |
| Abstrakt: |
In pursuit of a GABAA α5-subtype-selective inverse agonist to enhance cognition, a series of 6,7-dihydro-2-benzothiophen-4(5H)-ones has been identified as a novel class of GABAA receptor ligands. These thiophenes have higher binding affinity for the GABAA α5 receptor subtype compared to the GABAA α1, α2, and α3 subtypes, and several analogues exhibit high GABAA α5 receptor inverse agonism. 6,6-Dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (43) has been identified as a full inverse agonist at the GABAA α5 receptor and is functionally selective over the other major GABAA receptor subtypes. 43 readily penetrates into the CNS to give selective occupancy of GABAA α5 receptors. In addition, 43 enhances cognitive performance in rats in the delayed matching-to-place' Morris water maze test&sbd;a hippocampal-dependent memory task&sbd;without the convulsant or proconvulsant activity associated with nonselective, GABAA receptor inverse agonists. |
| Databáze: |
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