Synthesis of 1,3-di- and 1,3,4-trisubstituted 1,6-dihydro-6-iminopyridazines as competitive antagonists of insect GABA receptors

Abstract

Insect GABA receptors (GABARs) represent important targets for insecticides. Thirteen iminopyridazine GABA analogs were synthesized and evaluated for their antagonism of three cloned insect GABARs. Of the synthesized analogs, 4-[4-cyclobutyl-1,6-dihydro-6-imino-3-(2-naphthyl)pyridazin-1-yl]butyronitrile greatly reduced GABA-activated responses in small brown planthopper (SBP) and common cutworm (CC) GABARs at 100 µM. Removal of the cyclobutyl group did not affect the levels of inhibition in both GABARs, whereas it increased the inhibition levels in housefly (HF) GABARs to afford an analog with an IC₅₀ of 75.5 µM. 4-[3-(4-Biphenylyl)-1,6-dihydro-6-iminopyridazin-1-yl]butyronitrile and the 3-(2-fluoro-4-biphenylyl) congener exhibited >80% inhibition in SBP and CC GABARs at 100 µM. These analogs showed relatively potent antagonism of HF GABARs, with IC₅₀s of 37.9 µM and 42.3 µM, respectively. Ethyl 3-[3-(4-biphenylyl)-1,6-dihydro-6-iminopyridazin-1-yl]propylphosphonate was the most potent inhibitor of GABA-induced currents in HF GABARs, with an IC₅₀ of 18.8 µM. These findings suggest that the iminopyridazine analogs could be leads for the development of insecticides.