Novel 3-carboxy-and 3-phosphonopyrazoline amino acids as potent and selective NMDA receptor antagonists: Design, synthesis, and pharmacological characterization

Paola Conti, Andrea Pinto, Lucia Tamborini, Ulf Madsen, Birgitte Nielsen, Hans Bräuner-Osborne, Kasper B. Hansen, Elisa Landucci, Domenico E. Pellegrini-Giampietro, Giovambattista De Sarro, Eugenio Donato Di Paola, Carlo De Micheli

Research output: Contribution to journalArticlepeer-review

Abstract

The design and synthesis of new N1-substituted 3-carboxyand 3-phosphonopyrazoline and pyrazole amino acids that target the glutamate binding site of NMDA receptors are described. An analysis of the stereochemical requirements for high-affinity interaction with these receptors was performed. We identified two highly potent and selective competitive NMDA receptor antagonists, (5S,αR)-1 and (5S,αR)-4, which exhibit good in vitro neuroprotective activity and in vivo anticonvulsant activity by i.p. administration, suggesting that these molecules may have potential use as therapeutic agents.

Original languageEnglish
Pages (from-to)1465-1475
Number of pages11
JournalChemMedChem
Volume5
Issue number9
DOIs
StatePublished - Sep 3 2010

Keywords

  • 1,3-dipolar cycloaddition
  • Anticonvulsant activity
  • NMDA receptor antagonists
  • Neuroprotection
  • Pyrazolines

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