title: A novel N-methyl-D-aspartate receptor open channel blocker with in vivo neuroprotectant activity.
abstract: Excitotoxicity has been implicated in the etiology of ischemic stroke, chronic neurodegenerative disorders, and very recently, in glioma growth. Thus, the development of novel neuroprotectant molecules that reduce excitotoxic brain damage is vigorously pursued. We have used an ionic current block-based cellular assay to screen a synthetic combinatorial library of trimers of N-alkylglycines on the N-methyl-D-aspartate (NMDA) receptor, a well known molecular target involved in excitotoxicity. We report the identification of a family of N-alkylglycines that selectively blocked the NMDA receptor. Notably, compound 3,3-diphenylpropyl-N-glycinamide (referred to as N20C) inhibited NMDA receptor channel activity with micromolar affinity, fast on-off blockade kinetics, and strong voltage dependence. Molecule N20C did not act as a competitive glutamate or glycine antagonist. In contrast, saturation of the blocker binding site with N20C prevented dizolcipine (MK-801) blockade of the NMDA receptor, implying that both drugs bind to the same receptor site. The N-alkylglycine efficiently prevented in vitro excitotoxic neurodegeneration of cerebellar and hippocampal neurons in culture. Attenuation of neuronal glutamate/NMDA-induced Ca(2+) overload and subsequent modulation of the glutamate-nitric oxide-cGMP pathway seems to underlie N20C neuroprotection. Noteworthy, this molecule exhibited significant in vivo neuroprotectant activity against an acute, severe, excitotoxic insult. Taken together, these findings indicate that N-alkylglycine N20C is a novel, low molecular weight, moderate-affinity NMDA receptor open channel blocker with in vitro and in vivo neuroprotective activity, which, in due turn, may become a tolerated drug for the treatment of neurodegenerative diseases and cancer.
authors.affiliation: Centro de Biología Molecular y Celular, Universidad Miguel Hernández, Ed. Torregaitán, Avenida Ferrocaril s/n, 03202 Elche, Alicante, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.forename: Marc
authors.initials: M
authors.lastname: Humet
authors.forename: Asia M
authors.initials: AM
authors.lastname: Fernández
authors.forename: Carolina
authors.initials: C
authors.lastname: García-Martínez
authors.forename: Elvira
authors.initials: E
authors.lastname: Valera
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Merino
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Payá
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000641:Ammonia / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D014981:Xenopus
chemical_list: C459382:3,3-diphenylpropyl-N-glycinamide; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D009569:Nitric Oxide; D000641:Ammonia; D000242:Cyclic AMP; D006152:Cyclic GMP; D005998:Glycine