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NEUROPHARMACOLOGY

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

Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain (C.O., C.d.l.R., E.A., R.L., A.G.G., M.V., M.G.L.); Instituto de Química Orgánica General, Madrid, Spain (C.d.l.R., R.L., J.L.M.); Servicio de Farmacología Clínica, Hospital de la Princesa, Madrid, Spain (A.G.G.); and Instituto Universitario de Gerontología, Hospital de la Princesa, Madrid, Spain (M.G.L.)

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 µM. In the human neuroblastoma cell line SH-SY5Y, ITH4012 also reduced amyloid _25-35-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 µM) but has the additional property of acting as a calcium promotor, a property leading to neuroprotection through the induction of antiapoptotic proteins.

Address correspondence to: Mercedes Villarroya, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain. E-mail: mercedes.villarroya{at}uam.es