Competitive antagonism of insect GABA receptors by 4-substituted 5-(4-piperidyl)-3-isothiazolols

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 17; pp. 4637 - 4645
• Main Authors: Liu, Genyan, Furuta, Kenjiro, Nakajima, Hiromitsu, Ozoe, Fumiyo, Ozoe, Yoshihisa
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2014; Elsevier
• Subjects: 3-Isothiazolols; Animals; Binding, Competitive - drug effects; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Competitive antagonists; Dose-Response Relationship, Drug; Functional assays; GABA Antagonists - chemical synthesis; GABA Antagonists - chemistry; GABA Antagonists - pharmacology; Houseflies; Insect GABA receptors; Insecticidal activity; Insecticides - chemical synthesis; Insecticides - chemistry; Insecticides - pharmacology; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Receptors, GABA - metabolism; Science & Technology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Thio-4-PIOL; CC; SBP; DMSO; 3-Isothiazolols; FMP; Thio-4-PIOL; Insecticidal activity; Insect GABA receptors; Functional assays; Competitive antagonists; IC50; GABA; EC50; FLIPR; RDL; GABAR; HF; RDLR; HIGH-AFFINITY; RESIDUES CONTRIBUTE; DROSOPHILA CELL-LINE; INTERNATIONAL UNION; PHARMACOLOGY; MOLECULAR-CLONING; XENOPUS OOCYTES; GAMMA-AMINOBUTYRIC-ACID; BINDING POCKET; GATED CHLORIDE CHANNELS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.07.021

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.