Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity. / Liu, Genyan; Frølund, Bente; Ozoe, Fumiyo; Ozoe, Yoshihisa.

In: Insect Biochemistry and Molecular Biology, Vol. 66, 2015, p. 64-71.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Liu, G, Frølund, B, Ozoe, F & Ozoe, Y 2015, 'Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity', Insect Biochemistry and Molecular Biology, vol. 66, pp. 64-71. https://doi.org/10.1016/j.ibmb.2015.10.002

APA

Liu, G., Frølund, B., Ozoe, F., & Ozoe, Y. (2015). Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity. Insect Biochemistry and Molecular Biology, 66, 64-71. https://doi.org/10.1016/j.ibmb.2015.10.002

Vancouver

Liu G, Frølund B, Ozoe F, Ozoe Y. Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity. Insect Biochemistry and Molecular Biology. 2015;66:64-71. https://doi.org/10.1016/j.ibmb.2015.10.002

Author

Liu, Genyan ; Frølund, Bente ; Ozoe, Fumiyo ; Ozoe, Yoshihisa. / Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity. In: Insect Biochemistry and Molecular Biology. 2015 ; Vol. 66. pp. 64-71.

Bibtex

@article{5c1fb179da084fb2a38afb38fbb8c1ab,
title = "Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity",
abstract = "γ-Aminobutyric acid (GABA) receptors (GABARs) mediate fast inhibitory synaptic transmission and are also targets for drugs and insecticides. To better understand the molecular interactions of ligands with the orthosteric sites of GABARs, we examined 4-aryl/arylalkyl-5-(4-piperidyl)-3-isoxazolol, 4-aryl-5-(4-piperidyl)-3-isothiazolol, and 5-aryl-4-(4-piperidyl)-1-hydroxypyrazole for their antagonism with regard to three insect GABARs. The 3-isoxazolol was preferable to the 3-isothiazolol and 1-hydroxypyrazole in antagonism to common cutworm and housefly GABARs. Of the tested analogues, 4-(3-biphenylyl)-5-(4-piperidyl)-3-isoxazolol (2a) displayed the greatest antagonism for common cutworm and housefly GABARs, with IC50 values of 3.4 and 10.2 μM, respectively. In contrast to the antagonism of the two GABARs, 2a showed partial agonism for the case of small brown planthopper GABARs, with an EC50 value of 31.3 μM. Homology models and docking simulations revealed that a cation-π interaction between an analogue and an Arg residue in loop C or E of the orthosteric site is a key component of antagonism. This specific phenomenon was lacking in the interactions between 2a and the orthosteric site of small brown planthopper GABARs. These findings provide important insights into designing and developing novel drugs and insecticides.",
author = "Genyan Liu and Bente Fr{\o}lund and Fumiyo Ozoe and Yoshihisa Ozoe",
note = "Copyright {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",
year = "2015",
doi = "10.1016/j.ibmb.2015.10.002",
language = "English",
volume = "66",
pages = "64--71",
journal = "Insect Biochemistry and Molecular Biology",
issn = "0965-1748",
publisher = "Pergamon Press",

}

RIS

TY - JOUR

T1 - Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insect γ-aminobutyric acid receptors leading to functional selectivity

AU - Liu, Genyan

AU - Frølund, Bente

AU - Ozoe, Fumiyo

AU - Ozoe, Yoshihisa

N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.

PY - 2015

Y1 - 2015

N2 - γ-Aminobutyric acid (GABA) receptors (GABARs) mediate fast inhibitory synaptic transmission and are also targets for drugs and insecticides. To better understand the molecular interactions of ligands with the orthosteric sites of GABARs, we examined 4-aryl/arylalkyl-5-(4-piperidyl)-3-isoxazolol, 4-aryl-5-(4-piperidyl)-3-isothiazolol, and 5-aryl-4-(4-piperidyl)-1-hydroxypyrazole for their antagonism with regard to three insect GABARs. The 3-isoxazolol was preferable to the 3-isothiazolol and 1-hydroxypyrazole in antagonism to common cutworm and housefly GABARs. Of the tested analogues, 4-(3-biphenylyl)-5-(4-piperidyl)-3-isoxazolol (2a) displayed the greatest antagonism for common cutworm and housefly GABARs, with IC50 values of 3.4 and 10.2 μM, respectively. In contrast to the antagonism of the two GABARs, 2a showed partial agonism for the case of small brown planthopper GABARs, with an EC50 value of 31.3 μM. Homology models and docking simulations revealed that a cation-π interaction between an analogue and an Arg residue in loop C or E of the orthosteric site is a key component of antagonism. This specific phenomenon was lacking in the interactions between 2a and the orthosteric site of small brown planthopper GABARs. These findings provide important insights into designing and developing novel drugs and insecticides.

AB - γ-Aminobutyric acid (GABA) receptors (GABARs) mediate fast inhibitory synaptic transmission and are also targets for drugs and insecticides. To better understand the molecular interactions of ligands with the orthosteric sites of GABARs, we examined 4-aryl/arylalkyl-5-(4-piperidyl)-3-isoxazolol, 4-aryl-5-(4-piperidyl)-3-isothiazolol, and 5-aryl-4-(4-piperidyl)-1-hydroxypyrazole for their antagonism with regard to three insect GABARs. The 3-isoxazolol was preferable to the 3-isothiazolol and 1-hydroxypyrazole in antagonism to common cutworm and housefly GABARs. Of the tested analogues, 4-(3-biphenylyl)-5-(4-piperidyl)-3-isoxazolol (2a) displayed the greatest antagonism for common cutworm and housefly GABARs, with IC50 values of 3.4 and 10.2 μM, respectively. In contrast to the antagonism of the two GABARs, 2a showed partial agonism for the case of small brown planthopper GABARs, with an EC50 value of 31.3 μM. Homology models and docking simulations revealed that a cation-π interaction between an analogue and an Arg residue in loop C or E of the orthosteric site is a key component of antagonism. This specific phenomenon was lacking in the interactions between 2a and the orthosteric site of small brown planthopper GABARs. These findings provide important insights into designing and developing novel drugs and insecticides.

U2 - 10.1016/j.ibmb.2015.10.002

DO - 10.1016/j.ibmb.2015.10.002

M3 - Journal article

C2 - 26453818

VL - 66

SP - 64

EP - 71

JO - Insect Biochemistry and Molecular Biology

JF - Insect Biochemistry and Molecular Biology

SN - 0965-1748

ER -

ID: 147580970