title: Novel 3-carboxy- and 3-phosphonopyrazoline amino acids as potent and selective NMDA receptor antagonists: design, synthesis, and pharmacological characterization.
abstract: 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, (5S,alphaR)-1 and (5S,alphaR)-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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche P. Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. paola.conti@unimi.it
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Elisa
authors.initials: E
authors.lastname: Landucci
authors.forename: Domenico E
authors.initials: DE
authors.lastname: Pellegrini-Giampietro
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.forename: Eugenio
authors.initials: E
authors.lastname: Donato Di Paola
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001665:Binding Sites; D001667:Binding, Competitive; D015195:Drug Design; D051379:Mice; D008968:Molecular Conformation; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D018696:Neuroprotective Agents; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate