Structure-activity studies on the activity of a series of cyclopentane GABA analogues on GABAA receptors and GABA uptake.

A series of analogues of gamma-aminobutyric acid (GABA) has been investigated for GABA mimetic activity on the isolated guinea-pig ileum, facilitation of [3H]diazepam binding in rat brain membranes and inhibition of [3H]GABA uptake from rat brain cortical slices. The derivatives tested include six racemic amino acids, all of which contain a 'GABA backbone' with the conformation restricted by a cyclopentane or cyclopentene ring system. From the more potent analogues, five optically pure compounds, including (+)-(4S)-4-aminocyclopent-1-ene-1-carboxylic acid and its (-)-4R enantiomer, have also been assessed as GABA agonists. Of the racemic analogues, 4-aminocyclopent-1-ene-1-carboxylic acid and trans-3-aminocyclopentane-1-carboxylic acid were the most potent at GABAA receptors, while most of the analogues had considerable activity on GABA uptake. The individual resolved isomers of 4-aminocyclopent-1-ene-carboxylic acid and of trans-3-aminocyclopentane-1-carboxylic acid displayed great specificity for GABA receptor and GABA uptake sites. For example (+)-(4S)-4-aminocyclopent-1-ene-1-carboxylic acid was approximately twice as potent as GABA and about 600 times more active than the (-)-4R isomer on the guinea-pig ileum, while it was not significantly active as a GABA uptake inhibitor at 500 microM. On the other hand, its (-)-4R isomer was selective for inhibiting GABA uptake with an IC50 equal to that of racemic nipecotic acid.