Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease.
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.
Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. iqoc21@iqog.csic.es
José
J
Marco-Contelles
Rafael
R
León
Cristóbal
C
de los Ríos
Abdelouahid
A
Samadi
Manuela
M
Bartolini
Vincenza
V
Andrisano
Oscar
O
Huertas
Xavier
X
Barril
F Javier
FJ
Luque
María I
MI
Rodríguez-Franco
Beatriz
B
López
Manuela G
MG
López
Antonio G
AG
García
María do Carmo
Mdo C
Carreiras
Mercedes
M
Villarroya
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D013619:Tacrine / Q000031:analogs & derivatives*
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D002800:Cholinesterase Inhibitors; D004095:Dihydropyridines; D008024:Ligands; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D013619:Tacrine; C038806:1,4-dihydropyridine; D006861:Hydrogen Peroxide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002118:Calcium