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.
authors.affiliation: Division of Bioscience and Biotechnology, Course of Bioresources Science, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8553, Japan.
authors.forename: Genyan
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen Φ, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ozoe
authors.affiliation: Division of Bioscience and Biotechnology, Course of Bioresources Science, The United Graduate School of Agricultural Sciences, Tottori University, Tottori 680-8553, Japan; Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan. Electronic address: ozoe-y@life.shimane-u.ac.jp.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ozoe
mesh_terms: D000818:Animals; D018756:GABA Antagonists / Q000494:pharmacology*; D019476:Insect Proteins / Q000378:metabolism; D007313:Insecta / Q000187:drug effects* / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000494:pharmacology*; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C000590775:5-(4-piperidyl)-3-isothiazolol; D018756:GABA Antagonists; D019476:Insect Proteins; D007306:Insecticides; D008024:Ligands; D010880:Piperidines; D018079:Receptors, GABA; D013844:Thiazoles
keywords: 4-(3-Biphenylyl)-4-PIOL; Competitive antagonist; GABA; Insect GABA receptors; Insecticides; Partial agonist