Document Detail

Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: a kinetic analysis.
MedLine Citation:
PMID:  16540097     Owner:  NLM     Status:  MEDLINE    
The use of the antiepileptic drug, 4-aminobutyrate transaminase (GABA-T) inhibitor vigabatrin (VIGA), has been recently cautioned because it is associated to irreversible field defects from damage of the retina. Since novel GABA-T inhibitors might prove useful in epilepsy or other CNS pathologies as VIGA substitutes, the aim of the present investigation was to characterize the biochemical properties of some taurine analogues (TA) previously shown to act as GABA-T inhibitors. These include (+/-)piperidine-3-sulfonic acid (PSA), 2-aminoethylphosphonic acid (AEP), (+/-)2-acetylaminocyclohexane sulfonic acid (ATAHS) and 2-aminobenzenesulfonate (ANSA). Kinetic analysis of the activity of partially purified rabbit brain GABA-T in the presence of VIGA and TA showed that PSA and AEP caused a linear, mixed-type inhibition (Ki values 364 and 1010 microM, respectively), whereas VIGA, ANSA and ATAHS behaved like competitive inhibitors (Ki values 320, 434 and 598 microM, respectively). Among the compounds studied, only VIGA exerted a time-dependent, irreversible inhibition of the enzyme, with Ki and k(inact) values of 773 microM and 0.14 min(-1), respectively. Furthermore, the ability of VIGA and TA to enhance GABA-ergic transmission was assessed in rabbit brain cortical slices by NMR quantitative analysis. The results demonstrate that VIGA as well as all TA promoted a significant increase of GABA content. In conclusion, PSA, ANSA and ATAHS, reversible GABA-T inhibitors with Ki values close to that of VIGA, represent a new class of compounds, susceptible of therapeutic exploitation in many disorders associated with low levels of GABA in brain tissues.
Lorenzo Ricci; Maria Frosini; Nicola Gaggelli; Gianni Valensin; Fabrizio Machetti; Giampietro Sgaragli; Massimo Valoti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-02-28
Journal Detail:
Title:  Biochemical pharmacology     Volume:  71     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-04-20     Completed Date:  2006-05-25     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1510-9     Citation Subset:  IM    
Dipartimento di Scienze Biomediche, Sezione di Farmacologia, Università di Siena, viale A. Moro 2, lotto C, 53100 Siena, Italy.
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MeSH Terms
4-Aminobutyrate Transaminase / antagonists & inhibitors*,  metabolism
Aminoethylphosphonic Acid / chemistry,  pharmacology
Anticonvulsants / chemistry,  pharmacology*
Brain / drug effects*,  enzymology
Enzyme Inhibitors / pharmacology*
Piperidines / chemistry,  pharmacology
Sulfanilic Acids / chemistry,  pharmacology
Taurine / analogs & derivatives*
Vigabatrin / analogs & derivatives,  chemistry,  pharmacology*
Reg. No./Substance:
0/Anticonvulsants; 0/Enzyme Inhibitors; 0/Piperidines; 0/Sulfanilic Acids; 107-35-7/Taurine; 2041-14-7/Aminoethylphosphonic Acid; 60643-86-9/Vigabatrin; 72450-62-5/piperidine-4-sulfonic acid; 88-21-1/2-sulfanilic acid; EC Transaminase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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