Comparative Stereostructure‐Activity Studies on GABAA and GABAB Receptor Sites and GABA Uptake Using Rat Brain Membrane Preparations

: The affinities of a number of analogues of γ‐aminobutyric acid (GABA) for GABAA and GABAB receptor sites and GABA uptake were studied using rat brain membrane preparations. Studies on the (S)‐(+)‐and (R)‐(‐)‐isomers of baclofen, 3‐hydroxy‐4‐aminobutyric acid (3‐OH‐GABA), and 4,5‐dihydromuscimol (DHM) revealed different stereoselectivities of these synaptic mechanisms in vitro. Although (S)‐3‐OH‐GABA and, in particular, (S)‐DHM were more potent than the corresponding (R)‐isomers as inhibitors of GABAA binding, the opposite stereoselectivity was demonstrated for the GABAB binding sites. Thus, (R)‐3‐OH‐GABA and (R)‐baclofen were more potent than the (S)‐isomers as inhibitors of GABAB binding, (R)‐baclofen being some five times more potent than (R)‐3‐OH‐GABA. These two (R)‐isomers actually have opposite orientation of the substituents on the GABA backbones, suggesting that the lipophilic substituent of (R)‐baclofen interacts with a structural element of the GABAB receptor site different from that that binds the very polar hydroxy group of (R)‐3‐OH‐GABA. The O‐methylated analogue of 3‐OH‐GABA, 3‐methoxy‐4‐aminobutyric acid (3‐OCH3‐GABA), did not interact significantly with GABAB sites. The homoiogues of GABA, trans‐4‐aminocrotonic acid (trans‐ACA). muscimol, and 3‐OH‐GABA, that is, 5‐aminovaleric acid (DAVA), trans‐5‐aminopent‐2‐enoic acid, homomuscimol, and 3‐hydroxy‐5‐aminovaleric acid (3‐OH‐DAVA), respectively, were generally much weaker than the parent compounds, whereas 2‐hydroxy‐5‐aminovaleric acid (2‐OH‐DAVA) showed a significantly higher affinity for GABAB sites than the corresponding GABA analogue, 2‐hydroxy‐4‐aminobutyric acid (2‐OH‐GABA). The cyclized analogues of these amino acids, perhydrooxazine‐6‐carboxylic acid and isoxazolidine‐5‐carboxylic acid, respectively, were inactive.