Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease. Journal of medicinal chemistry [J Med Chem] Journal article | | Title | Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease. | | Author(s) | Marco-Contelles J, León R, de los Ríos C, Samadi A, Bartolini M, Andrisano V, Huertas O, Barril X, Luque FJ, Rodríguez-Franco MI, López B, López MG, García AG, Carreiras Mdo C, Villarroya M | | Institution | Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. iqoc21@iqog.csic.es | | Source | J Med Chem 2009 May 14; 52(9):2724-32. | | MeSH | Acetylcholinesterase
Alzheimer Disease
Amyloid beta-Protein
Blood-Brain Barrier
Butyrylcholinesterase
Calcium
Calcium Channel Blockers
Catalytic Domain
Cell Death
Cell Line, Tumor
Cholinesterase Inhibitors
Cytosol
Dihydropyridines
Humans
Hydrogen Peroxide
Kinetics
Ligands
Models, Molecular
Peptide Fragments
Permeability
Tacrine
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19374444 |
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