INHIBITION OF GABA UPTAKE IN RAT BRAIN SLICES BY NIPECOTIC ACID, VARIOUS ISOXAZOLES AND RELATED COMPOUNDS

Abstract

Abstract —A variety of isoxazoles structurally related to muscimol (3‐hydroxy‐5‐aminomethylisoxazole) were tested as inhibitors of the uptake of GABA and some other amino acids in rat brain slices, and of the activity of the GABA‐metabolizing enzymes l ‐glutamate 1‐carboxylyase and GABA:2‐oxo‐glutarate aminotransferase. A bicyclic derivative, 4,5,6,7‐tetrahydroisoxazolo[4,5‐ c ]pyridin‐3‐ol, proved to be a more potent inhibitor of GABA uptake than muscimol. Structure‐activity studies on this derivative, which appeared to be a competitive inhibitor of GABA uptake, led to the findings that nipecotic acid (piperidine‐3‐carboxylic acid) is a powerful non‐competitive inhibitor of GABA uptake, and that perhydro‐1,2‐oxazine‐6‐carboxylic acid is a relatively weak competitive inhibitor of GABA uptake.