Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA
2012
Rahman, Mohammad Mostafizur | Akiyoshi, Yuki | Furutani, Shogo | Matsuda, Kazuhiko | Furuta, Kenjiro | Ikeda, Izumi | Ozoe, Yoshihisa
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 100μM 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 100μM, respectively. The 4-biphenyl and 4-phenoxyphenyl analogues showed moderate inhibition at 10μM in these receptors, although the inhibition at 100μM 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 500μM 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.
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