TY - JOUR
T1 - Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease
AU - Marco-Contelles, José
AU - León, Rafael
AU - De Los Ríos, Cristóbal
AU - Samadi, Abdelouahid
AU - Bartolini, Manuela
AU - Andrisano, Vincenza
AU - Huertas, Oscar
AU - Barril, Xavier
AU - Luque, F. Javier
AU - Rodríguez-Franco, María I.
AU - López, Beatriz
AU - López, Manuela G.
AU - García, Antonio G.
AU - Carreiras, María Do Carmo
AU - Villarroya, Mercedes
PY - 2009/5/14
Y1 - 2009/5/14
N2 - 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.
AB - 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.
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U2 - 10.1021/jm801292b
DO - 10.1021/jm801292b
M3 - Article
C2 - 19374444
AN - SCOPUS:65649142161
SN - 0022-2623
VL - 52
SP - 2724
EP - 2732
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -