Action of analogues on ?-aminobutyric acid recognition sites in rat brain.

With a view to finding potential GABA-mimetics, the effects of a number of structural analogues of GABA were studied on three parameters associated with GABA neural transmission of rat brain. These were (1) the binding of [(3)H]GABA to its receptor, (2) the binding of [(3)H]GABA to its transporter (sodium-dependent binding), and (3) the activity of GABA aminotransferase. Thirteen of the 21 compounds tested competitively inhibited both the low and the high affinity GABA receptor binding components. The most potent inhibitors were morpholinopropane sulphonic acid (MOPS) and aminoethylthiosulphonic acid (AETS). All of the compounds were markedly less effective in inhibiting the high affinity GABA receptor binding system than the low affinity system. The effect of each of the inhibitors was measured on [(3)H]diazepam receptor binding. Only 6-(morpholinomethyl)kojic acid, kojic amine, 1-piperidinepropane sulphonic acid and 4(4?-azido-benzoimidylamino)butanoic acid (ABBA) were able to induce a stimulation of binding. Four of the inhibitors of [(3)H]GABA binding were able to appreciably reduce GABA-induced enhancement of diazepam binding. These were N-(2-nitro,4-azidophenyl)aminopropane sulphonic acid, 8-amino-1-napthalene sulphonic acid, narcotine-N-oxide and 5-phenyl-2-pyrrolepropionic acid. These results demonstrate that MOPS and AETS are good inhibitors of GABA receptor binding although there is no other evidence that they might be agonists since they have no effect on diazepam receptor binding. Based on their ability to block GABA-induced stimulation of diazepam binding ABBA, 8-amino-1-naphthalene sulphonic acid and 5-phenyl-2-pyrrolepropionic acid may possess antagonistic properties. ABBA was the only compound to inhibit sodium-dependent [(3)H]GABA binding. None of the compounds had an effect on the activity of GABA aminotransferase. From this study at least two analogues, MOPS and AETS, have emerged that hold potential as GABA-mimetics. Also, the three GABA recognition sites of rat brain have been shown to possess marked pharmacological differences.