Relationships of structure to binding of gamma-aminobutyric acid (GABA) and related compounds with the GABA and benzodiazepine receptors.

The relationship of the structure of gamma-aminobutyric acid (GABA) and 45 related compounds to their binding with the GABA and benzodiazepine (BDZ) receptors was investigated. In the course of evaluating the cross-reactivity of the 45 GABA-related compounds in a GABA radioreceptor assay (GABA-RRA) using [3H]GABA and rat brain synaptic membranes, it became clear that for the molecule to react with GABA-receptors the amino group must be free, but that the carboxy group is not essential. It was also demonstrated that the molecule lost its cross-reactivity if the distance between the alpha-carbon and the amino group exceeded a certain limit, and, additionally, that the cross-reacting potency depended on the stereospecificity of the compound. When the cross-reactivity of GABA related compounds with the GABA receptor was compared with their enhancement of BDZ receptor affinity, a parallelism was found between the two actions. Between d-gamma-amino-beta-hydroxybutyric acid (d-GABOB) and 1-GABOB, however, no difference was found in the BDZ receptor affinity-enhancing effect, although there was a large difference in the cross-reactivity in the GABA-RRA. This indicates that the stereospecificity of the beta-carbon is crucial for the binding of the molecule to the GABA receptor but not essential for its binding to the BDZ receptor, suggesting that the GABA receptor and the BDZ receptor each recognize a different site of the molecule.