Synthesis and evaluation of novel aromatic substrates and competitive inhibitors of GABA aminotransferase

• Published in: Bioorganic & medicinal chemistry 2008-05, Vol.18 (10), p.3122-3125
• Main Authors: Clift, Michael D., Silverman, Richard B.
• Format: Article
• Language: English
• Subjects: 4-Aminobutyrate Transaminase - antagonists & inhibitors; 4-Aminobutyrate Transaminase - chemistry; Analytical, structural and metabolic biochemistry; Aromatic amino acid; Binding, Competitive; Biological and medical sciences; Computer modeling; Computer Simulation; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; GABA-AT; Hydrocarbons, Aromatic - chemical synthesis; Hydrocarbons, Aromatic - chemistry; Hydrocarbons, Aromatic - pharmacology; Inhibitor; Medical sciences; Miscellaneous; Molecular Structure; Pharmacology. Drug treatments; Substrate of GABA-AT; Transferases; γ-Aminobutyric acid; γ-Aminobutyric acid aminotransferase
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.10.060

The design, synthesis, and evaluation of novel γ-aminobutyric acid aminotransferase (GABA-AT) inhibitors and inactivators can lead to the discovery of new GABA-related therapeutics. To this end, a series of aromatic amino acid compounds was synthesized to aid in the design of new inhibitors and inactivators of GABA-AT. All compounds were tested as competitive inhibitors of GABA-AT. The amino acids with benzylic amines were also tested as substrates for GABA-AT. It was found that these compounds were all poor competitive inhibitors of GABA-AT, but some were substrates of the enzyme, suggesting their utility as scaffolds for potential GABA-AT mechanism-based inactivators. Computer modeling was used to rationalize the substrate activity of the various compounds.