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Registro de acceso cerrado Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease

Autor :Marco Contelles, José Luis
León, Rafael
de los Ríos, Cristóbal
Samadi, Abdelouahid
Bartolini, Manuela
Andrisano, Vincenza
Huertas, Oscar
Barril, Xavier
Luque, F. Javier
Rodríguez Franco, María Isabel
López, Beatriz
López, Manuela G.
García, Antonio G.
do Carmo Carreiras, María
Villarroya, Mercedes
Fecha de publicación :2009
Editor:American Chemical Society
Citación :Journal of Medicinal Chemistry 52 : 2724–2732 (2009)
Resumen:Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ( 15 nM) is associated to a 30.7 ( 8.6% inhibition of the proaggregating action of AChE on the A and a moderate inhibition of A self-aggregation (34.9 ( 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.
Versión del editor:http://dx.doi.org/10.1021/jm801292b
URI :http://hdl.handle.net/10261/36491
DOI:10.1021/jm801292b
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