| New substrates and inhibitors of gamma-aminobutyric acid aminotransferase containing bioisosteres of the carboxylic acid group: design, synthesis, and biological activity. | |
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MedLine Citation:
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PMID: 16263300 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A series of potential substrates of gamma-aminobutyric acid aminotransferase (GABA-AT) with lipophilic bioisosteres of the carboxylic acid group (2-7) were synthesized and tested. Most of the synthesized compounds showed substrate activities with GABA-AT; 1H-tetrazole-5-propanamine (6) was the best of those tested. The potential time-dependent inhibitor of GABA-AT, 1H-tetrazole-5-(alpha-vinyl-propanamine) (8), was designed based on the structures of 6 and the antiepilepsy drug vigabatrin (4-aminohex-5-enoic acid, 1). The synthesized compound 8 showed time-dependent inhibition of GABA-AT, but its potency is lower than that of vigabatrin. Methylation of the tetrazole group in 8 resulted in loss of time-dependent activity, suggesting that the tetrazole ring, the carboxylate bioisostere, exists in its deprotonated form in the enzyme active site. |
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Authors:
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Hai Yuan; Richard B Silverman |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2005-11-02 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry Volume: 14 ISSN: 0968-0896 ISO Abbreviation: Bioorg. Med. Chem. Publication Date: 2006 Mar |
Date Detail:
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Created Date: 2006-01-23 Completed Date: 2006-05-02 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9413298 Medline TA: Bioorg Med Chem Country: England |
Other Details:
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Languages: eng Pagination: 1331-8 Citation Subset: IM |
Affiliation:
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Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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4-Aminobutyrate Transaminase
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antagonists & inhibitors* Anticonvulsants / chemical synthesis*, pharmacology Binding Sites Carboxylic Acids / chemistry* Enzyme Inhibitors / chemical synthesis*, pharmacology Kinetics Models, Chemical Tetrazoles / chemistry Vigabatrin / pharmacology gamma-Aminobutyric Acid / chemistry* |
| Grant Support | |
ID/Acronym/Agency:
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GM66132/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anticonvulsants; 0/Carboxylic Acids; 0/Enzyme Inhibitors; 0/Tetrazoles; 288-94-8/1H-tetrazole; 56-12-2/gamma-Aminobutyric Acid; 60643-86-9/Vigabatrin; EC 2.6.1.19/4-Aminobutyrate Transaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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