Novel insecticidal 1,6‐dihydro‐6‐iminopyridazine derivatives as competitive antagonists of insect RDL GABA receptors

Abstract

BACKGROUND: The ionotropic γ-aminobutyric acid (GABA) receptor (iGABAR) is an important target for insecticides and parasiticides. Our previous studies showed that competitive antagonists (CAs) of insect iGABARs have the potential to be used for developing novel insecticides and that the structural modification of gabazine (a representative CA of mammalian iGABARs) could lead to the identification of novel CAs of insect iGABARs.RESULTS: In the present study, a novel series of 1,3-di-and 1,3,5-trisubstituted 1,6-dihydro-6-iminopyridazines (DIPs) was designed using a versatile strategy and synthesized using facile methods. Electrophysiological studies showed that several target DIPs (30 ∼M) exhibited excellent antagonistic activities against common cutworm and housefly iGABARs consisting of RDL subunits. The IC 50 values of 3-(4-methoxyphenyl), 3-(4-trifluoromethoxyphenyl), 3-(4-biphenylylphenyl), 3-(2-naphthyl), 3-(3,4-methylenedioxyphenyl), and 3,5-(4-methoxyphenyl) analogs ranged from 2.2 to 24.8 ∼M. Additionally, several 1,3-disubstituted DIPs, especially 3-(4-trifluoromethoxyphenyl) and 3-(3,4-methylenedioxyphenyl) analogs, exhibited moderate insecticidal activity against common cutworm larvae, with >60% mortality at a concentration of 100 mg kg −1 . Molecular docking studies showed that the oxygen atom on the three-substituted aromatic ring could form a hydrogen bond with Arg254, which may enhance the activity of these DIPs against housefly iGABARs.CONCLUSION: This systematic study indicated that the presence of a carboxyl side chain shorter by one methylene than that of gabazine at the 1-position of the pyridazine ring is effective for maintaining the stable binding of these DIPs in insect iGABARs.Our study provides important information for the design of novel insect iGABAR CAs.

Mechanistic insights into the selectivity of bicyclophosphorothionate antagonists for housefly versus rat GABA receptors

“…[13][14][15] After many years of insect GABAR research, it has been confirmed that (i) the amino acid sequences of RDLs have a high degree of similarity to those of mammalian GABA A R subunits, (ii) the RDL subunit can form a functional, homomeric GABA-gated chloride channel that pharmacologically resembles native insect GABARs, and (iii) the insect GABARs composed of RDL subunits (RDLRs) constitute a relevant target for insecticides. 16 However, the research into insect GABARs lies behind that of mammalian GABARs, particularly in mechanistic aspects.…”

“…Four subunits or subunit‐like proteins of insect ionic GABARs are known to date in various insects: RDL Resistance to dieldrin (RDL), GABA and glycine‐like receptor of Drosophila (GRD), Ligand‐gated chloride channel homolog 3 (LCCH3), and Dmel/CG8916 orthologs 13–15 . After many years of insect GABAR research, it has been confirmed that (i) the amino acid sequences of RDLs have a high degree of similarity to those of mammalian GABA A R subunits, (ii) the RDL subunit can form a functional, homomeric GABA‐gated chloride channel that pharmacologically resembles native insect GABARs, and (iii) the insect GABARs composed of RDL subunits (RDLRs) constitute a relevant target for insecticides 16 . However, the research into insect GABARs lies behind that of mammalian GABARs, particularly in mechanistic aspects.…”