Inhibition and substrate activity of conformationally rigid vigabatrin analogues with gamma-aminobutyric acid aminotransferase.
Several cyclopentene GABA analogues were synthesized as conformationally rigid analogues of the epilepsy drug vigabatrin and tested as inhibitors and substrates of gamma-aminobutyric acid aminotransferase (GABA-AT). None of these compounds produced time-dependent inhibition. (1R, 4S)-(+)-4-Amino-2-cyclopentene-1-carboxylic acid ((+)-3), (4R)-(-)-4-amino-1-cyclopentene-1-carboxylic acid ((-)-4), and d, l-3-amino-1-cyclopentene-1-carboxylic acid (6) are good substrates. The K(m) and k(cat) values for the latter two compounds are very similar to those of GABA, suggesting that they bind in an orientation similar to that of GABA. The K(m) value for (+)-3 is 24 times lower than that for GABA, although its k(cat) value is only one-fourth that for GABA; nonetheless, it is a better substrate for GABA-AT than is GABA. All of these compounds, as well as the enantiomers of 3 and 4 and d, l-trans-4-amino-2-cyclopentene-1-carboxylic acid (5), are competitive inhibitors of GABA-AT. These results demonstrate the effects of the carboxylate group orientation and the stereochemistry of the amino and carboxylate groups on the substrate activity and inhibitor activity, and this should be important to the future design of inhibitors of GABA-AT.
Qiu
J
J
Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, USA.
Pingsterhaus
J M
JM
Silverman
R B
RB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D000598:Amino Acids, Cyclic; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020888:Vigabatrin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*
C401394:4-amino-1-cyclopentene-1-carboxylic acid; C401393:4-amino-2-cyclopentene-1-carboxylic acid; D000596:Amino Acids; D000598:Amino Acids, Cyclic; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin