New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties
| Autor: | Xavier Barril, Antonio G. García, Oscar Huertas, F. Javier Luque, Mercedes Villarroya, Rafael León, Cristóbal de los Ríos, Manuela G. López, José Marco-Contelles |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Dihydropyridines Magnetic Resonance Spectroscopy Calcium Channels L-Type Spectrophotometry Infrared Cell Survival Stereochemistry Clinical Biochemistry Pharmaceutical Science chemistry.chemical_element Calcium Biochemistry Neuroprotection Mass Spectrometry Inhibitory Concentration 50 chemistry.chemical_compound Cell Line Tumor Drug Discovery medicine Animals Humans Molecular Biology biology Voltage-dependent calcium channel Organic Chemistry Dihydropyridine Depolarization Calcium Channel Blockers Acetylcholinesterase Kinetics Neuroprotective Agents chemistry Enzyme inhibitor Tacrine biology.protein Molecular Medicine Cholinesterase Inhibitors Reactive Oxygen Species medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 16:7759-7769 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2008.07.005 |
| Popis: | In 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]naphthyridine-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. |
| Databáze: | OpenAIRE |
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