Novel 3-carboxy- and 3-phosphonopyrazoline amino acids as potent and selective NMDA receptor antagonists: design, synthesis, and pharmacological characterization.
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.
Conti
Paola
P
Dipartimento di Scienze Farmaceutiche P. Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. paola.conti@unimi.it
Pinto
Andrea
A
Tamborini
Lucia
L
Madsen
Ulf
U
Nielsen
Birgitte
B
Bräuner-Osborne
Hans
H
Hansen
Kasper B
KB
Landucci
Elisa
E
Pellegrini-Giampietro
Domenico E
DE
De Sarro
Giovambattista
G
Donato Di Paola
Eugenio
E
De Micheli
Carlo
C
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
D000596:Amino Acids; D000927:Anticonvulsants; D018696:Neuroprotective Agents; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate