RESUMEN
A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.
Asunto(s)
Bencimidazoles/síntesis química , Antagonistas de Aminoácidos Excitadores/síntesis química , Fármacos Neuroprotectores/síntesis química , Propionatos/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Arteriopatías Oclusivas/complicaciones , Bencimidazoles/química , Bencimidazoles/metabolismo , Bencimidazoles/farmacología , Unión Competitiva , Encéfalo/metabolismo , Encéfalo/patología , Enfermedades de las Arterias Carótidas/complicaciones , Evaluación Preclínica de Medicamentos , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/etiología , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratones , Modelos Moleculares , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Organofosfonatos , Propionatos/química , Propionatos/metabolismo , Propionatos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas F344 , Receptores de N-Metil-D-Aspartato/metabolismo , EstereoisomerismoRESUMEN
A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.