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

Posted June 8th, 2010 by pschmidtke
TitleTacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease
Publication TypeJournal Article
Year of Publication2009
AuthorsMarco-Contelles, J, Leon R, de los Rios C, Samadi A, Bartolini M, Andrisano V, Huertas O, Barril X, Luque FJ, Rodriguez-Franco MI, Lopez B, Lopez MG, Garcia AG, Mdo CC, Villarroya M
JournalJournal of medicinal chemistry
Volume52
Issue9
Pagination2724 - 2732
Date Published2009/05/14/
KeywordsAcetylcholinesterase/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
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 (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.