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

• Published in: Journal of medicinal chemistry 2009-05, Vol.52 (9), p.2724-2732
• Main Authors: Marco-Contelles, José, León, Rafael, de los Ríos, Cristóbal, Samadi, Abdelouahid, Bartolini, Manuela, Andrisano, Vincenza, Huertas, Oscar, Barril, Xavier, Luque, F. Javier, Rodríguez-Franco, María I, López, Beatriz, López, Manuela G, García, Antonio G, do Carmo Carreiras, María, Villarroya, Mercedes
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Biological and medical sciences; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Butyrylcholinesterase - metabolism; Calcium - metabolism; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; Catalytic Domain; Cell Death - drug effects; Cell Line, Tumor; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - metabolism; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Cytosol - drug effects; Cytosol - metabolism; Dihydropyridines - chemistry; Dihydropyridines - metabolism; Dihydropyridines - pharmacology; Dihydropyridines - therapeutic use; Humans; Hydrogen Peroxide - metabolism; Kinetics; Ligands; Medical sciences; Models, Molecular; Neuropharmacology; Neuroprotective agent; Peptide Fragments - metabolism; Permeability - drug effects; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Tacrine - analogs & derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801292b

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 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.