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

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Choi S, Silverman RB

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

J Med Chem. 2002 Sep 26;45(20):4531-9.

PubMed ID

12238932 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Vigabatrin	4-aminobutyrate aminotransferase, mitochondrial	Ki (nM)	850000	N/A	N/A	Details