Potent Gamma-aminobutyric Acid Research Articles

Esters of isoguvacine as potential prodrugs.

The syntheses of the methyl ester, butyl ester, (ethoxycarbonyl)methyl ester, and 11 (acyloxy)methyl esters of the potent gamma-aminobutyric acid agonist isoguvacine (1,2,3,6-tetrahydropyridine-4-carboxylic acid) and described. The chemical stability of the esters and their in vitro rates of hydrolysis under approximately physiological conditions by nonspecific esterases from human serum were examined. A selected number of the esters were tested for antagonism of convulsions induced by bicuculline, isoniazide, and by electroschock. While in the compounds showed only weak activities in the bicuculline and isoniazide tests, a good correlation between in vitro rates of enzymatic hydrolysis and the time of onset of the antagonism of the electroschock-induced convulsions could be found.

Binding of [3H]-muscimol, a potent gamma-aminobutyric acid receptor agonist, to membranes of the bovine retina.

1 The binding of [3H]-muscimol, a potent gamma-aminobutyric acid (GABA) receptor agonist, to crude membrane preparations of bovine retina was studied, using a filtration method to isolate membrane-bound ligand. 2 Specific binding was found to be saturable and occurred at two binding sites with affinity constants of 4.3 nM and 38.2 nM. 3 Binding was sodium-independent, enhanced by both freezing and Triton X-100 treatment but abolished with sodium laurylsulphate. 4 The binding sites demonstrated a high degree of pharmacological specificity, GABA being a potent displacer of [3H]-muscimol. 5 A higher degree of [3H]-muscimol binding was associated with subcellular fractions enriched with photoreceptor synaptosomes rather than with fractions enriched with conventional synaptosomes.