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Tacripyrines, the First Tacrine−Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

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journal contribution
posted on 14.05.2009, 00:00 by José Marco-Contelles, Rafael León, Cristóbal de los Ríos, Abdelouahid Samadi, Manuela Bartolini, Vincenza Andrisano, Oscar Huertas, Xavier Barril, F. Javier Luque, María I. Rodríguez-Franco, Beatriz López, Manuela G. López, Antonio G. García, María do Carmo Carreiras, Mercedes Villarroya
Tacripyrines (114) 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 Aβ and a moderate inhibition of Aβ 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.