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Novel 3‐Carboxy‐ and 3‐Phosphonopyrazoline Amino Acids as Potent and Selective NMDA Receptor Antagonists: Design, Synthesis, and Pharmacological Characterization
Author(s) -
Conti Paola,
Pinto Andrea,
Tamborini Lucia,
Madsen Ulf,
Nielsen Birgitte,
BräunerOsborne Hans,
Hansen Kasper B.,
Landucci Elisa,
PellegriniGiampietro Domenico E.,
De Sarro Giovambattista,
Donato Di Paola Eugenio,
De Micheli Carlo
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000184
Subject(s) - nmda receptor , neuroprotection , chemistry , glutamate receptor , receptor , in vivo , amino acid , stereochemistry , pharmacology , in vitro , competitive antagonist , pyrazole , biochemistry , antagonist , biology , microbiology and biotechnology
The design and synthesis of new N1‐substituted 3‐carboxy‐ and 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, (5 S ,α R )‐ 1 and (5 S ,α R )‐ 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.