| Research Abstract |
To obtain information on the three-dimensional structure of noncompetitive antagonist-binding site of the γ-aminobutyric acid (GABA) receptor, molecular probes were synthesized and examined for their abilities to bind to the site and structure-activity relationships.
1. Analysis with probe 1, picrodendrins
Picrodendrins, plant-derived terpenoids, act as GABA antagonists. Some of the compounds showed binding activity toward both rat and housefly receptors, while other compounds exhibited selectivity for housefly receptors. Our three-dimensional binding site model, consisting of four subsites, proved to successfully explain the manifestation of picrodendrins' activity and selectivity.
2. Analysis with probe 2, bicyclophosphorothionates
Bicyclophosphorothionates, bearing appropriate 3- and 4-substituents, exhibited selectivity for housefly GABA receptors, suggesting structural differences between rat and housefly GABA receptors. Three-dimensional quantitative structure-activity relationship analysis of these compounds led to defining the region of putative subsites B and C in housefly receptors.
3. Analysis with probe 3, acyclic esters and ethers
Most compounds of this group displayed antagonist activity for rat GABA receptors, while they had only low potency for housefly receptors. These compounds are supposed to interact with three of four subsites, and so an interaction with the other subsite (i.e., B) could be of importance for antagonists to exhibit selectivity.
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