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New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties

Posted June 8th, 2010 by pschmidtke
TitleNew tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties
Publication TypeJournal Article
Year of Publication2008
AuthorsLeon, R, de los Rios C, Marco-Contelles J, Huertas O, Barril X, Luque FJ, Lopez MG, Garcia AG, Villarroya M
JournalBioorganic & medicinal chemistry
Volume16
Issue16
Pagination7759 - 7769
Date Published2008/08/15/
KeywordsAcetylcholinesterase/chemistry/metabolism; Animals; Calcium/antagonists & inhibitors/metabolism; Calcium Channel Blockers/chemical synthesis/chemistry/pharmacology; Calcium Channels, Infrared; Tacrine/analogs & derivatives/chemical synthesis/chemistry/pharmacology, L-Type/metabolism; Cell Line, Molecular; Neuroprotective Agents/chemical synthesis/chemistry/pharmacology; Reactive Oxygen Species/antagonists & inhibitors/metabolism; Spectrophotometry, Tumor; Cell Survival/drug effects; Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology; Dihydropyridines/chemical synthesis/chemistry/pharmacology; Humans; Inhibitory Concentration 50; Kinetics; Magnetic Resonance Spectroscopy; Mass Spectr
AbstractIn this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1,8]naphthy ridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca(2+)] elevation elicited by K⊕ depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer's disease.