Inactivation and inhibition of γ-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues

Sun Choi, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Four cyclohexene analogues of γ-aminobutyric acid (GABA) and β-alanine were designed as conformationally rigid analogues of the epilepsy and drug addiction drug vigabatrin and as potential mechanism-based inactivators of γ-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.

Original languageEnglish (US)
Pages (from-to)4531-4539
Number of pages9
JournalJournal of Medicinal Chemistry
Volume45
Issue number20
DOIs
StatePublished - Sep 26 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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