Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA

Rahman, Mohammad Mostafizur; Akiyoshi, Yuki; Furutani, Shogo; Matsuda, Kazuhiko; Furuta, Kenjiro; Ikeda, Izumi; Ozoe, Yoshihisa

doi:10.1016/j.bmc.2012.07.049

Cited by 17 publications

(23 citation statements)

References 35 publications

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“…Our previous study showed that gabazine (R 1 =COOH, R 2 =4-methoxyphenyl, and R 3 =H) exhibited 76.4% and 60.2% inhibition of the GABA response in SBP and CC GABARs, respectively, at 100 µM. 31) Therefore, the cyclobutyl group is detrimental in this case.…”

Section: Antagonism Of Sbp and CC Gabarsmentioning

confidence: 99%

“…31) To determine the mode of antagonism of synthesized IPs, in particular, IPs with cyano and phosphonate functionalities at the end of the side chain, GABA concentration-response relationships were examined in HF GABARs expressed in Xenopus oocytes in the presence and absence of 7d and 8. A rightward shift was observed in the concentrationresponse curves in the presence of the cyanide 7d (40 µM) and the ethyl phosphonate 8 (20 µM), indicating the competitive antagonism of these compounds (Fig.…”

Section: Mode Of Antagonismmentioning

confidence: 99%

“…28,32) FMP assays were performed using these cell lines as described in a previous report. 31) In these assays, changes in membrane potential were determined based on changes in the fluorescence of an FMP dye. Briefly, the cells were washed and suspended in a buffered saline (120 mM of NaCl, 5 mM of KCl, 2 mM of CaCl 2 , 8 mM of MgCl 2 , 10 mM of HEPES, and 32 mM of sucrose, adjusted pH to 7.2 with NaOH).…”

Section: Fmp Assays Drosophila S2 Cell Lines Stably Expressing Small mentioning

confidence: 99%

“…Inhibition data of gabazine (Gz) are taken from our previous report. 31) tests, we used fluorometric imaging plate reader (FLIPR) membrane potential (FMP) technology. 35,36) Application of GABA to Drosophila cell lines stably expressing SBP and CC GABARs induces chloride ion efflux and membrane depolarization, which is then recorded with a fluorescent dye loaded in the cells.…”

Section: Antagonism Of Sbp and CC Gabarsmentioning

confidence: 99%

“…1), and we observed enhanced antagonism of insect GABARs. 31) These findings prompted the synthesis of other analogs. Here, we report the synthesis of 1,3-di-and 1,3,4-trisubstituted IPs and their antagonism of GABARs cloned from two agricultural insect pest species and a sanitary insect species.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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 IC 50 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 IC 50 s 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 IC 50 of 18.8 µM. These findings suggest that the iminopyridazine analogs could be leads for the development of insecticides.

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Section: Antagonism Of Sbp and CC Gabarsmentioning

confidence: 99%

Section: Mode Of Antagonismmentioning

confidence: 99%

Section: Fmp Assays Drosophila S2 Cell Lines Stably Expressing Small mentioning

confidence: 99%

Section: Antagonism Of Sbp and CC Gabarsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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KNOCKDOWN OF THE IONOTROPIC γ‐AMINOBUTYRIC ACID RECEPTOR (GABAR) RDL GENE DECREASES FIPRONIL SUSCEPTIBILITY OF THE SMALL BROWN PLANTHOPPER, Laodelphax striatellus (HEMIPTERA: DELPHACIDAE)

Niu

et al. 2015

Arch Insect Biochem Physiol

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Insect γ-aminobutyric acid receptors (GABARs) are important molecular targets of cyclodiene and phenylpyrazole insecticides. Previously GABARs encoding rdl (resistant to dieldrin) genes responsible for dieldrin and fipronil resistance were identified in various economically important insect pests. In this study, we cloned the open reading frame cDNA sequence of rdl gene from fipronil-susceptible and fipronil-resistant strains of Laodelphax striatellus (Lsrdl). Sequence analysis confirmed the presence of a previously identified resistance-conferring mutation. Different alternative splicing variants of Lsrdl were noted. Injection of dsLsrdl reduced the mRNA abundance of Lsrdl by 27-82%, and greatly decreased fipronil-induced mortality of individuals from both susceptible and resistant strains. These data indicate that Lsrdl encodes a functional RDL subunit that mediates susceptibility to fipronil. Additionally, temporal and spatial expression analysis showed that Lsrdl was expressed at higher levels in eggs, fifth-instar nymphs, and female adults than in third-instar and fourth-instar nymphs. Lsrdl was predominantly expressed in the heads of 2-day-old female adults. All these results provide useful background knowledge for better understanding of fipronil resistance related ionotropic GABA receptor rdl gene expressed variants and potential functional differences in insects.

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

Liu

Zhou

Zhang

et al. 2022

Pest Management Science

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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.

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Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA

Cited by 17 publications

References 35 publications

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

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

KNOCKDOWN OF THE IONOTROPIC γ‐AMINOBUTYRIC ACID RECEPTOR (GABAR) RDL GENE DECREASES FIPRONIL SUSCEPTIBILITY OF THE SMALL BROWN PLANTHOPPER, Laodelphax striatellus (HEMIPTERA: DELPHACIDAE)

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

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