Block of neuronal voltage-dependent K+ channels by diacylhydrazine insecticides.
RH-5849 (1,2-dibenzoyl-1-tert-butylhydrazine), a novel insect growth regulator, also produces acute neurotoxic symptoms by selectively blocking the maintained voltage-dependent K+ current (IK) in nerve and muscle Salgado (1992). The effects of RH-5849 and an analog were examined on IK channels in internally-perfused crayfish giant axons. For bilaterally applied RH-5849, the concentration needed for 50% block (IC50) was 79 +/- 6 microM (mean +/- SEM, n = 3), with a Hill coefficient near 2. Block was independent of membrane potential, but dependent on time, with a speed proportional to concentration, suggesting an open channel block mechanism. In addition to their effects on IK, both diacylhydrazines were much weaker blockers of the voltage-dependent sodium current (INa). RH-5849 blocked IK from either side of the membrane, and was more potent when applied bilaterally. When RH-5849 was introduced inside the axon and internal perfusion was halted, IK increased within a few minutes to the control level, indicating that the compound diffused freely through the membrane and bound to a receptor within the plane of the membrane. The permeability coefficients measured in the stopped-flow experiments indicate that diacylhydrazines can diffuse readily throughout the body of a poisoned insect, consistent with the rapid onset of central nervous system symptoms following injection. The octanol:water partition coefficient of RH-5849 increased sharply from 145 to 258 at aqueous concentrations between 5 and 10 microM, suggesting that a new phase, possibly micellar, is formed in the octanol phase. This may be responsible for the anomalously high Hill coefficients for the channel blocking activity of the diacylhydrazines.
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Rohm and Haas Company, Spring House, Pennsylvania 19477, USA.
D000818:Animals; D003400:Astacoidea; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D006793:Houseflies; D006834:Hydrazines / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers
C112804:1-benzoyl-2-(2-bromobenzoyl)-tert-butylhydrazine; D006834:Hydrazines; D007306:Insecticides; D026902:Potassium Channel Blockers; C056565:1,2-dibenzoyl-tert-butylhydrazine