具有杀虫活性的4,5-取代的3-异恶唑醇作为家蝇GABA受体的竞争性拮抗剂,Journal of Agricultural and Food Chemistry

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具有杀虫活性的4,5-取代的3-异恶唑醇作为家蝇GABA受体的竞争性拮抗剂
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2015-07-13 00:00:00 , DOI: 10.1021/acs.jafc.5b01843
Genyan Liu ₁ , Fumiyo Ozoe ₂ , Kenjiro Furuta _{1,

2} , Yoshihisa Ozoe _{1,

2}

Affiliation

昆虫GABA受体（GABAR）由五个RDL亚基组成，是杀虫剂的重要靶标。合成了包括麝香酚类似物在内的一系列4,5-二取代的3-异恶唑，并检查了它们对非洲爪蟾卵母细胞中表达的家蝇GABAR的四个剪接变体（ac，ad，bc和bd）的活性。在所有四个剪接变体中，Muscimol均比GABA更有力，但合成的类似物在家蝇GABAR中不表现出拮抗作用，而表现出拮抗作用。在麝香酚的4位上引入双环芳族基团，并在5位上同时用氨基甲酰基取代氨基甲基，从而得到6个4-芳基-5-氨基甲酰基-3-异恶唑醇，这些化合物表现出显着的与IC增强拮抗作用交流变体的低微摩尔范围内有_50个值。ac和bc变体的100μM类似物对GABA诱导的电流的抑制作用比ad和bd变体的抑制作用大约1.5–4倍。4-（3-Biphenylyl）-5-carbamoyl-3-isoxazolol显示出竞争性拮抗作用，在ac，bc，ad和bd变体中，IC ₅₀值分别为30、34、107和96μM，并且表现出中等程度的拮抗作用对家蝇的杀虫活性，LD ₅₀值为5.6 nmol /蝇。这些发现表明，这些3-异恶唑醇类似物是用于设计和开发靶向家蝇GABAR正构位点的杀虫剂的新型先导化合物。

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4,5-Substituted 3-Isoxazolols with Insecticidal Activity Act as Competitive Antagonists of Housefly GABA Receptors

The insect GABA receptor (GABAR), which is composed of five RDL subunits, represents an important target for insecticides. A series of 4,5-disubstituted 3-isoxazolols, including muscimol analogues, were synthesized and examined for their activities against four splice variants (ac, ad, bc, and bd) of housefly GABARs expressed in Xenopus oocytes. Muscimol was a more potent agonist than GABA in all four splice variants, whereas synthesized analogues did not exhibit agonism but rather antagonism in housefly GABARs. The introduction of bicyclic aromatic groups at the 4-position of muscimol and the simultaneous replacement of the aminomethyl group with a carbamoyl group at the 5-position to afford six 4-aryl-5-carbamoyl-3-isoxazolols resulted in compounds that exhibited significantly enhanced antagonism with IC₅₀ values in the low micromolar range in the ac variant. The inhibition of GABA-induced currents by 100 μM analogues was approximately 1.5–4-fold greater in the ac and bc variants than in the ad and bd variants. 4-(3-Biphenylyl)-5-carbamoyl-3-isoxazolol displayed competitive antagonism, with IC₅₀ values of 30, 34, 107, and 96 μM in the ac, bc, ad, and bd variants, respectively, and exhibited moderate insecticidal activity against houseflies, with an LD₅₀ value of 5.6 nmol/fly. These findings suggest that these 3-isoxazolol analogues are novel lead compounds for the design and development of insecticides that target the orthosteric site of housefly GABARs.

更新日期：2015-07-13

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