Syntheses and evaluation of fluorinated conformationally restricted analogues of GABA as potential inhibitors of GABA aminotransferase.
Inhibition of gamma-aminobutyric acid aminotransferase (GABA-AT) could raise the concentration of GABA, an inhibitory neurotransmitter in the human brain, and could have therapeutic applications for a variety of neurological diseases including epilepsy. Four fluorine-containing analogues of GABA with conformations restricted by a cyclohexane ring system were designed and synthesized, but unlike some of their five-membered ring counterparts, minimal inhibition of GABA-AT was observed. It is likely that the rigid chair conformation of these compounds cannot be accommodated well in the enzyme's active site.
Wang
Zhiyong
Z
Department of Chemistry, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL 60208-3113, USA.
Silverman
Richard B
RB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry*; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005461:Fluorine; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase