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

AuthorsMarco-Contelles, José ; León, Rafael; de los Ríos, Cristóbal; Samadi, Abdelouahid ; Bartolini, Manuela; Andrisano, Vincenza; Huertas, Oscar; Barril, Xavier; Luque Garriga, Francisco Javier; Rodríguez-Franco, María Isabel ; López, Beatriz; López, Manuela G.; García, Antonio G.; do Carmo Carreiras, María; Villarroya, Mercedes
Issue Date2009
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 52 : 2724–2732 (2009)
AbstractTacripyrines (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.
Publisher version (URL)http://dx.doi.org/10.1021/jm801292b
Appears in Collections:(IQM) Artículos
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