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Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type
- Source :
- Journal of medicinal chemistry. 44(10)
- Publication Year :
- 2001
-
Abstract
- 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.
- Subjects :
- Carotid Artery Diseases
Male
Models, Molecular
Benzimidazole
Drug Evaluation, Preclinical
Organophosphonates
Arterial Occlusive Diseases
Pharmacology
In Vitro Techniques
Neuroprotection
Binding, Competitive
Receptors, N-Methyl-D-Aspartate
chemistry.chemical_compound
Mice
Radioligand Assay
In vivo
Drug Discovery
Animals
chemistry.chemical_classification
Ligand binding assay
Brain
Infarction, Middle Cerebral Artery
Stereoisomerism
Rats, Inbred F344
Amino acid
Rats
Neuroprotective Agents
chemistry
Excitatory Amino Acid Antagonists
Molecular Medicine
NMDA receptor
Benzimidazoles
Propionates
Subjects
Details
- ISSN :
- 00222623
- Volume :
- 44
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....06f1f6d0a7297481045b278250f3b2c3