| Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs of phenytoin. | |
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MedLine Citation:
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PMID: 10411214 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glycine, which has weak anticonvulsant properties, has been shown to potentiate the activity of several antiepileptic drugs but not phenytoin. Recently, studies have shown that N-(benzyloxycarbonyl)glycine (Z-glycine) antagonized seizures more than glycine in addition to possessing activity in the maximal electroshock test, a convulsive model in which glycine is inactive. In the present study esters of 3-hydroxymethylphenytoin, a phenytoin prodrug, and Z-glycine as well as the homologous N-(benzyloxycarbonyl)-omega-amino acids, Z-beta-alanine and Z-gamma-aminobutyric acid (Z-GABA), were prepared and tested for their anticonvulsant and acute neurotoxic activities. The phenytoin prodrugs were obtained by esterification of bis(2-oxo-3-oxazolidinyl)-phosphinic acid chloride-mediated esterification of 3-hydroxymethylphenytoin with the respective N-benzyloxycarbonyl-protected amino acid. The Z-glycine-phenytoin ester was the most active anticonvulsant derivative. Compared with phenytoin the compound exhibited a decreased median effective dose (ED50) in the MES test and an increased median toxic dose (TD50), resulting in an significantly improved protective index expressed as the ratio between TD50 and ED50. The present data suggest that covalent binding of phenytoin to Z-glycine results in an improved pharmacological profile of the drug. |
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Authors:
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G K Scriba; D M Lambert |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of pharmacy and pharmacology Volume: 51 ISSN: 0022-3573 ISO Abbreviation: J. Pharm. Pharmacol. Publication Date: 1999 May |
Date Detail:
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Created Date: 1999-09-09 Completed Date: 1999-09-09 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0376363 Medline TA: J Pharm Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 549-53 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Chemistry, University of Münster, Germany. scriba@uni-muenster.de |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticonvulsants / chemical synthesis*, pharmacology Glycine / analogs & derivatives, chemical synthesis, pharmacology Phenytoin / analogs & derivatives*, chemistry, pharmacology Prodrugs / chemical synthesis*, pharmacology Rats |
| Chemical | |
Reg. No./Substance:
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0/Anticonvulsants; 0/Prodrugs; 1138-80-3/N-benzyloxycarbonylglycine; 56-40-6/Glycine; 57-41-0/Phenytoin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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