title: Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA.
abstract: A series of 4-(6-imino-3-aryl/heteroarylpyridazin-1-yl)butanoic acids were synthesized and examined for antagonism of GABA receptors from three insect species. When tested against small brown planthopper GABA receptors, the 3,4-methylenedioxyphenyl and the 2-naphthyl analogues showed complete inhibition of GABA-induced fluorescence changes at 100 μM in assays using a membrane potential probe. Against common cutworm GABA receptors, these analogues displayed approximately 86% and complete inhibition of GABA-induced fluorescence changes at 100 μM, respectively. The 4-biphenyl and 4-phenoxyphenyl analogues showed moderate inhibition at 10 μM in these receptors, although the inhibition at 100 μM was not complete. Against American cockroach GABA receptors, the 4-biphenyl analogue exhibited the greatest inhibition (approximately 92%) of GABA-induced currents, when tested at 500 μM using a patch-clamp technique. The second most active analogue was the 2-naphthyl analogue with approximately 85% inhibition. The 3-thienyl analogue demonstrated competitive inhibition of cockroach GABA receptors. Homology modeling and ligand docking studies predicted that hydrophobic 3-substituents could interact with an accessory binding site at the orthosteric binding site.
authors.affiliation: Division of Bioscience and Biotechnology, United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8553, Japan.
authors.forename: Mohammad Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.forename: Yuki
authors.initials: Y
authors.lastname: Akiyoshi
authors.forename: Shogo
authors.initials: S
authors.lastname: Furutani
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Matsuda
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Furuta
authors.forename: Izumi
authors.initials: I
authors.lastname: Ikeda
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ozoe
mesh_terms: D000818:Animals; D018756:GABA Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D019476:Insect Proteins / Q000378:metabolism*; D007313:Insecta / Q000187:drug effects* / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives*
chemical_list: D018756:GABA Antagonists; D019476:Insect Proteins; D007306:Insecticides; D011724:Pyridazines; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid