title: Competitive antagonism of insect GABA receptors by 4-substituted 5-(4-piperidyl)-3-isothiazolols.
abstract: γ-Aminobutyric acid (GABA) receptors are important targets of parasiticides/insecticides. Several 4-substituted analogs of the partial GABAA receptor agonist 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) were synthesized and examined for their antagonism of insect GABA receptors expressed in Drosophila S2 cells or Xenopus oocytes. Thio-4-PIOL showed weak antagonism of three insect GABA receptors. The antagonistic activity of Thio-4-PIOL was enhanced by introducing bicyclic aromatic substituents into the 4-position of the isothiazole ring. The 2-naphthyl and the 3-biphenylyl analogs displayed antagonist potencies with half maximal inhibitory concentrations in the low micromolar range. The 2-naphthyl analog induced a parallel rightward shift of the GABA concentration-response curve, suggesting competitive antagonism by these analogs. Both compounds exhibited weak insecticidal activities against houseflies. Thus, the orthosteric site of insect GABA receptors might be a potential target site of insecticides.
authors.affiliation: Division of Bioscience and Biotechnology, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8553, Japan.
authors.forename: Genyan
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Bioscience and Biotechnology, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8553, Japan; Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Furuta
authors.affiliation: Division of Bioscience and Biotechnology, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8553, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ozoe
authors.affiliation: Division of Bioscience and Biotechnology, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8553, Japan; Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan. Electronic address: ozoe-y@life.shimane-u.ac.jp.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ozoe
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006793:Houseflies; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000590775:5-(4-piperidyl)-3-isothiazolol; D018756:GABA Antagonists; D007306:Insecticides; D010880:Piperidines; D018079:Receptors, GABA; D013844:Thiazoles
keywords: 3-Isothiazolols; Competitive antagonists; Functional assays; Insect GABA receptors; Insecticidal activity; Thio-4-PIOL