title: Non-competitive GABA antagonists: probing the mechanisms of their selectivity for insect versus mammalian receptors.
abstract: A great variety of non-competitive antagonists of ionotropic gamma-aminobutyric acid (GABA) receptors have been reported. While they are structurally diverse, there are common features in their structures. Thus, it was hypothesized that they bind to an identical site in different or overlapping orientations, and this hypothesis was validated by three-dimensional structure-activity relationship (3D-QSAR) analysis using receptor-binding data. Meanwhile, although most antagonists are highly toxic to both vertebrates and invertebrates, several classes of antagonists, such as nor-diterpene lactone picrodendrins, phenyl heterocyclic compounds and disubstituted bicyclophosphorothionates, were found to exhibit selectivity for housefly versus rat GABA receptors. To probe their selectivity mechanisms, the 3D-QSAR method was applied to the three classes of antagonists. This revealed several important differences that might be related to the selectivity of antagonists between the structures of the non-competitive antagonist-binding sites of housefly and rat GABA receptors.
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan. ozoe-y@life.shimane-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Ozoe
authors.forename: M
authors.initials: M
authors.lastname: Akamatsu
mesh_terms: D000818:Animals; D001665:Binding Sites; D001685:Biological Factors; D018756:GABA Antagonists / Q000737:chemistry / Q000378:metabolism*; D007313:Insecta / Q000502:physiology*; D008322:Mammals / Q000502:physiology*; D008958:Models, Molecular; D015394:Molecular Structure; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001685:Biological Factors; D018756:GABA Antagonists; D018079:Receptors, GABA