Insect ?-aminobutyric acid (GABA) receptors (GABARs) contain important target sites for existing and emerging insecticides. Phenylpyrazole insecticides such as fipronil act as noncompetitive GABAR antagonists or GABA-gated chloride channel blockers. Isoxazoline and benzamide ectoparasiticide/insecticides disrupt the function of GABARs by acting at a distinct site(s). Iminopyridazines (IPs) such as gabazine competitively antagonize the function of GABA. However, the potencies of IPs at insect GABARs have not fully been studied. Therefore, we synthesized IPs and examined their antagonistic activity against GABARs cloned from four insect species. Gabazine, which has R1 = C6H4OCH3-4, R2 = COOH, R3 = H, showed moderate inhibition (60-70% at 100 �M) of GABA responses in Laodelphax striatellus (Ls) and Spodoptera litura (Sl) GABARs, whereas it was a weak antagonist in Periplaneta americana and Musca domestica GABARs. Introduction of bulkier aromatic rings such as the 2-naphthyl and 4-biphenyl groups in R1 increased the potency. The CN and P(=O)(OH)(OC2H5) groups proved to be bioisosteres of COOH in R2. Cyclo-C4H7 in R3 was detrimental when R2 = COOH, whereas it was not unfavorable in Ls- and Sl-GABARs when R2 = CN. Some of the synthesized IPs showed insecticidal activities.

Synthesis of iminopyridazines and their potencies as competitive antagonists in insect GABA receptors

248th National Meeting (2014)

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