| Inactivation and inhibition of gamma-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues. | |
| | |
MedLine Citation:
|
PMID: 12238932 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Four cyclohexene analogues of gamma-aminobutyric acid (GABA) and beta-alanine were designed as conformationally rigid analogues of the epilepsy and drug addiction drug vigabatrin and as potential mechanism-based inactivators of gamma-aminobutyric acid aminotransferase (GABA-AT). The corresponding cyclopentene analogues were previously reported to be inhibitors, but not inactivators, of GABA-AT (Qiu, J.; Pingsterhaus, J.; Silverman, R. B. J. Med. Chem. 1999, 42, 4725-4728). cis-3-Aminocyclohex-4-ene-1-carboxylic acid (3) and cis-2-aminocyclohex-3-ene-1-carboxylic acid (5) showed time- and concentration-dependent, irreversible inactivation of GABA-AT. In both cases, the inactivations are protected by substrate, indicating that they are active site-directed. trans-3-Aminocyclohex-4-ene-1-carboxylic acid (4) and trans-2-aminocyclohex-3-ene-1-carboxylic acid (6) are not inactivators but are competitive reversible inhibitors of GABA-AT. Unlike the cyclopentene analogues, there appears to be sufficient ring flexibility to allow inactivation to occur. The orientation of the carboxylic and amino groups of these analogues is important for their binding to GABA-AT. Molecular modeling of GABA-AT with 3-6 and molecular dynamics simulations with vigabatrin bound provide rationalizations for the inhibitory properties of these compounds. |
| | |
Authors:
|
Sun Choi; Richard B Silverman |
Publication Detail:
|
Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Journal of medicinal chemistry Volume: 45 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2002 Sep |
Date Detail:
|
Created Date: 2002-09-19 Completed Date: 2002-10-21 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
|
Languages: eng Pagination: 4531-9 Citation Subset: IM |
Affiliation:
|
Department of Chemistry and the Drug Discover Program, Northwestern University, Evanston, Illinois 60208-3113, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
4-Aminobutyrate Transaminase
/
antagonists & inhibitors* Binding Sites Chromatography, High Pressure Liquid Cyclohexanes / chemical synthesis*, chemistry Enzyme Activation / drug effects Enzyme Inhibitors / chemical synthesis*, chemistry Models, Molecular Molecular Conformation Structure-Activity Relationship Vigabatrin / analogs & derivatives*, chemical synthesis*, chemistry |
| Grant Support | |
ID/Acronym/Agency:
|
NS15703/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Cyclohexanes; 0/Enzyme Inhibitors; 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
Previous Document: Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma ...
Next Document: Design, synthesis, and immunostimulatory properties of CpG DNAs containing alkyl-linker substitution...