β-Lactams: A New Class of Conformationally-Rigid Inhibitors of γ-Aminobutyric Acid Aminotransferase

Abstract

A structural similarity of several monobactams (2–4), 3-aminonocardicinic acid (6), 6-aminopenicillanic acid (7), 7-aminocephalosporanic acid (8), and 7-aminodesacetoxycephalosporanic acids (9, 10) to γ-aminobutyric acid (GABA) and to known inhibitors and substrates of GABA aminotransferase is described. Because of this, the above-mentioned compounds were tested as competitive inhibitors and as inactivators of pig brain GABA aminotransferase. All of the compounds were competitive inhibitors of GABA aminotransferase. On the basis of the inhibitory potency of these conformationally-rigid GABA analogues it is hypothesized that GABA is bound at the active site with its amino and carboxylate groups in a syn orientation. None of the compounds inactivates GABA aminotransferase. These β-lactam analogues represent the first examples of a new class of inhibitors of GABA aminotransferase.

Key Words: :

• β-Lactams
• γ-aminobutyric acid
• γ-aminobutyric acid aminotransferase
• monobactams
• penicillins
• cephalosporins