title: ITH4012 (ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate), a novel acetylcholinesterase inhibitor with "calcium promotor" and neuroprotective properties.
abstract: Ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8] naphthyridine-3-carboxylate (ITH4012) is a novel tacrine derivative that can reduce cell death induced by various compounds with different mechanisms of action, such as thapsigargin (reticular stress), H2O2 (free radicals), and veratridine (calcium overload), in bovine chromaffin cell. Cell viability, quantified as lactic dehydrogenase release, was significantly reduced by ITH4012 at concentrations ranging from 0.01 to 3 microM. In the human neuroblastoma cell line SH-SY5Y, ITH4012 also reduced amyloid beta25-35-induced apoptosis, determined by flow cytometry. ITH4012 caused a slight elevation in the cytosolic concentration of Ca2+ in fura 2-loaded bovine chromaffin cells, which could be related to the induction of protein synthesis relevant for cell survival. Blockade of protein synthesis by cycloheximide or blockade of Bcl-2's active site with HA14-1 (ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) reversed the cytoprotective action of ITH4012. Furthermore, exposure of bovine chromaffin cells for 24 or 48 h to neuroprotective concentrations of this compound enhanced, nearly 3-fold, the expression of the antiapoptotic protein Bcl-2. In conclusion, ITH4012 is a tacrine derivative that maintains acetylcholinesterase-inhibiting activity (IC50=0.8 microM) but has the additional property of acting as a calcium promotor, a property leading to neuroprotection through the induction of antiapoptotic proteins.
authors.affiliation: Instituto Teófilo Hernando, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Camilo
authors.initials: C
authors.lastname: Orozco
authors.forename: Cristobal
authors.initials: C
authors.lastname: de Los Rios
authors.forename: Esperanza
authors.initials: E
authors.lastname: Arias
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Jose L
authors.initials: JL
authors.lastname: Marco
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D019439:Chromaffin Cells; D019610:Cytoprotection / Q000187:drug effects; D004338:Drug Combinations; D004347:Drug Interactions; D005609:Free Radicals / Q000494:pharmacology; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014701:Veratridine / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D005609:Free Radicals; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C492670:ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzo(1,8)naphthyridine-3-carboxylate; D013619:Tacrine; D019284:Thapsigargin; D014701:Veratridine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium