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

José Marco-Contelles, Rafael León, Cristóbal De Los Ríos, Abdelouahid Samadi, Manuela Bartolini, Vincenza Andrisano, Oscar Huertas, Xavier Barril, F. Javier Luque, María I. Rodríguez-Franco, Beatriz López, Manuela G. López, Antonio G. García, María Do Carmo Carreiras, Mercedes Villarroya

Research output: Contribution to journalArticlepeer-review

142 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)2724-2732
Number of pages9
JournalJournal of Medicinal Chemistry
Volume52
Issue number9
DOIs
Publication statusPublished - May 14 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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