@article {258, title = {Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer{\textquoteright}s disease}, journal = {Journal of medicinal chemistry}, volume = {52}, year = {2009}, month = {2009/05/14/}, pages = {2724 - 2732}, 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 (IC(50) 105 +/- 15 nM) is associated to a 30.7 +/- 8.6\% inhibition of the proaggregating action of AChE on the Abeta and a moderate inhibition of Abeta 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 Ca(2+) channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.}, keywords = {Acetylcholinesterase/metabolism; Alzheimer Disease/drug therapy/enzymology/metabolism/pathology; Amyloid beta-Protein/metabolism; Blood-Brain Barrier/drug effects/metabolism; Butyrylcholinesterase/metabolism; Calcium/metabolism; Calcium Channel Blockers/c, Molecular; Peptide Fragments/metabolism; Permeability/drug effects; Tacrine/analogs \& derivatives, Tumor; Cholinesterase Inhibitors/chemistry/metabolism/pharmacology/therapeutic use; Cytosol/drug effects/metabolism; Dihydropyridines/chemistry/metabolism/pharmacology/therapeutic use; Humans; Hydrogen Peroxide/metabolism; Kinetics; Ligands; Models}, author = {Marco-Contelles,J. and Leon,R. and Rios,C. de los and Samadi,A. and Bartolini,M. and Andrisano,V. and Huertas,O. and Barril, Xavier and F. J. Luque and Rodriguez-Franco,M. I. and Lopez,B. and Lopez,M. G. and Garcia,A. G. and Mdo,C. Carreiras and Villarroya,M.} }