Alam Mohammad Sayed, Kajiki Ryu, Hanatani Hiromi, Kong Xiangyu, Ozoe Fumiyo, Matsui Yoshihisa, Matsumura Fumio, Ozoe Yoshihisa
Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan.
J Agric Food Chem. 2006 Feb 22;54(4):1361-72. doi: 10.1021/jf052773i.
To study the interaction of phenylheterocycles with gamma-aminobutyric acid (GABA) receptors, 4- or 5-alkyl(or phenyl)-1-phenyl-1H-1,2,3-triazoles were synthesized and examined for their ability to inhibit the specific binding of [3H]-4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a noncompetitive antagonist, to the housefly and rat GABA receptors, as well as to the beta3 subunit homo-oligomer of the human GABA receptor investigated as a model receptor. 4-Substituted 1-phenyl-1H-1,2,3-triazoles were found to be more potent competitive inhibitors than the 5-substituted regioisomers in the case of all receptors. The 4-tert-butyl or 4-n-propyl analogue of 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole exhibited the highest level of inhibition of [3H]EBOB binding to all receptors. Most of the synthesized analogues were more active in terms of the inhibition of EBOB binding to the housefly and human beta3 GABA receptors than to the rat receptor. The 4-cyclohexyl analogue showed the highest (185-fold) housefly versus rat receptor selectivity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis demonstrated that both the 4-trifluoromethyl-2,6-dichloro substitution on the phenyl ring and a small, bulky, hydrophobic substituent at the 4-position of the triazole ring played significant roles in conferring high potency in cases involving the housefly and human beta3 receptors. The human beta3 receptor resembled the housefly receptor in terms of their recognition of phenyltriazoles, whereas 3D-QSAR analysis revealed a slight difference between the two receptors in terms of their mechanisms of recognition of the para-substituent on the phenyl moiety. Some of the triazoles synthesized here exhibited insecticidal activity, which was correlated with their ability to inhibit [3H]EBOB binding to the housefly receptor. Thus, 1-phenyl-1H-1,2,3-triazoles with the appropriate substituents exert insecticidal activity by selectively acting at the site for noncompetitive antagonism of insect GABA receptors.
为了研究苯基杂环与γ-氨基丁酸（GABA）受体的相互作用，合成了4-或5-烷基（或苯基）-1-苯基-1H-1,2,3-三唑，并检测它们抑制非竞争性拮抗剂[3H]-4'-乙炔基-4-正丙基双环邻苯二甲酸酯（EBOB）与家蝇和大鼠GABA受体以及作为模型受体研究的人GABA受体β3亚基同型寡聚体特异性结合的能力。在所有受体中，发现4-取代的1-苯基-1H-1,2,3-三唑比5-取代的区域异构体是更有效的竞争性抑制剂。1-(2,6-二氯-4-三氟甲基苯基)-1H-1,2,3-三唑的4-叔丁基或4-正丙基类似物对[3H]EBOB与所有受体的结合表现出最高水平的抑制。大多数合成类似物在抑制EBOB与家蝇和人β3 GABA受体结合方面比与大鼠受体结合更具活性。4-环己基类似物表现出最高的（185倍）家蝇与大鼠受体选择性。三维定量构效关系（3D-QSAR）分析表明，苯环上的4-三氟甲基-2,6-二氯取代以及三唑环4位上的小的、庞大的、疏水取代基在涉及家蝇和人β3受体的情况下赋予高效能方面发挥了重要作用。人β3受体在识别苯基三唑方面与家蝇受体相似，而3D-QSAR分析表明这两种受体在识别苯基部分对位取代基的机制方面存在细微差异。这里合成的一些三唑表现出杀虫活性，这与其抑制[3H]EBOB与家蝇受体结合的能力相关。因此，具有适当取代基的1-苯基-1H-1,2,3-三唑通过选择性作用于昆虫GABA受体非竞争性拮抗位点发挥杀虫活性。
