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.
Novel 3-carboxy- and 3-phosphono-pyrazoline amino acids acting as potent and selective NMDA receptor antagonists: design, synthesis and pharmacological characterization / P. Conti, A. Pinto, L. Tamborini, U. Madsen, B. Nielsen, H. Bräuner Osborne, K.B. Hansen, E. Landucci, D.E. Pellegrini Giampietro, G. De Sarro, E. Donato Di Paola, C. De Micheli. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 5:9(2010 Sep), pp. 1465-1475. [10.1002/cmdc.201000184]
Novel 3-carboxy- and 3-phosphono-pyrazoline amino acids acting as potent and selective NMDA receptor antagonists: design, synthesis and pharmacological characterization
P. Conti
Primo
;A. PintoSecondo
;L. Tamborini;C. De MicheliUltimo
2010
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.File | Dimensione | Formato | |
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