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Title: Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease
Authors: 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
Issue Date: 2009
Publisher: American Chemical Society
Abstract: 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.
Publisher version (URL): http://dx.doi.org/10.1021/jm801292b
URI: http://hdl.handle.net/10261/36491
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Citation: Journal of Medicinal Chemistry 52 : 2724–2732 (2009)
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