Substituted Benzyl Chrysanthemates Research Articles

Quantitative structure-Activity studies of pyrethroids: 28. Type differentiation of action-potential changes in crayfish giant axons caused by substituted benzyl chrysanthemates and pyrethrates

The neurophysiological actions of variously substituted benzyl (1R)-trans-chrysanthemates and (1R)-trans-(E)-pyrethrates on the membrane potential of crayfish giant axons were observed by use of an intracellular microelectrode. The compounds were classified into three types according to their effects: deceleration of the falling phase of the action potential (type A), elevation of the depolarizing afterpotential (type B), and a combination of these effects (type C). The effects of substituents on the benzyl-benzene ring of the alcohol moiety on the type differentiation of actionpotential changes were examined by such statistical procedures as linear discriminant and logistic regression analyses with physicochemical substituent parameters. Logistic regression analysis was especially efficient in type classification. The most important substituent factors governing the type differentiation were steric bulk and electronic property. With increases in the bulkiness of substituents in terms of the van der Waals volume, the compound tended to change in its effects in the order of type A, type C, and type B. The greater the electron-withdrawing property, the greater was the tendency of compounds to be classified as type B.

Quantitative structure-activity studies of pyrethroids: 23. Rate of decrease in sodium tail currents induced by substituted benzyl chrysanthemates and pyrethrates in crayfish giant axons

The effects of pyrethroids, meta-substituted benzyl esters of (1 R)- trans-chrysanthemic and (1 R)- trans-( E)-pyrethric acids, on sodium currents were examined with crayfish giant axons perfused internally. The sodium currents were measured with step depolarization under voltage clamp conditions by the sucrose gap method. The compounds decreased the rate of fall in the tail current that was observed upon step repolarization of the membrane. Variations in the potency to decrease the rate of fall (the tail-current potency) were quantitatively analyzed by use of physicochemical and structural parameters of the aromatic substituents and regression analysis. Structural effects were common to both series of compounds. The introduction of substituents with a phenyl group into the benzyl benzene ring was favorable for the activity. The tail-current potency was also governed by steric dimensions of the substituents in terms of STERIMOL parameters. The aromatic substituents had an optimum width for the potency. The shorter the substituents, the higher was the tail-current potency. Variations in the insecticidal potency of chrysanthemates and pyrethrates against American cockroaches were related linearly with the tail-current potency when the transport factors of compounds were separated by use of the hydrophobicity parameter. The higher the tail-current potency, the higher the insecticidal potency.

Quantitative structure-activity studies of pyrethroids: Physicochemical properties and the rate of development of the residual and tail sodium currents in crayfish giant axon

The effects of 28 pyrethroids including variously substituted benzyl chrysanthemates and pyrethrates and their related compounds on sodium currents were examined in internally perfused giant axons of crayfish under voltage clamp conditions. The compounds increased the steady-state sodium current and induced a residual current during step depolarization of the axonal membrane. They also induced a tail current upon step repolarization. Each of the ratios of the residual and tail sodium currents to the transient peak sodium current at each measurement increased with time after the start of the internal application of the compounds until a steady level was reached. The rate constants of the development of the two kinds of sodium currents, residual and tail, in terms of the ratios were estimated by use of first-order kinetics and had a linear relationship for this series of compounds. Variations in each of these rate constants among compounds were parabolically related with the hydrophobicity of the molecule, giving a common optimum log P ( P, the partition coefficient in the 1-octanol/water system) at about 4.6. The rate of development of the residual and tail currents is probably decided by the penetration rate of the compounds to the target site(s).

Effect of substituted benzyl chrysanthemates on sodium and potassium currents in the crayfish giant axon

The effects of substituted benzyl (1 R)- trans-chrysanthemates on sodium and potassium currents were studied in voltage-clamped crayfish giant axons. The o-SO 2Me derivative decelerated the rate of the falling phase of the action potential (type A effect), and the p-SO 2Me derivative elevated the depolarizing afterpotential (type B effect). The o-SO 2Me derivative inhibited the inactivation of sodium channels. The time constant of the inactivation of sodium channels affected by the ortho derivative was 5–10 times that of the unaffected channels. The fraction of channels affected compared to the total sodium channels progressively increased during the administration of the drug. Voltage-sensitive potassium channels also were blocked progressively. The p-SO 2Me derivative markedly slowed down the inactivation and induced a large residual current during depolarization. The time constant of the inactivation of sodium channels affected by this drug was 50–100 times that in control axons. Upon repolarization, a large tail current was observed, indicating that the restoration of gating groups responsible for the activation to the nonconducting position on repolarization also was suppressed in some affected channels. The m-CN derivative, which had a mixed effect of both types A and B on the action potential, caused both moderate slowing of the inactivation of some sodium channels and induction of the residual current. During the administration of this drug, a small tail current was observed upon step repolarization. We concluded that the type A effect on action potential is due to moderate slowing of the inactivation of the sodium channels and blocking of some fraction of voltage-sensitive potassium channels, and that the type B effect is due to extremely slow inactivation of sodium channels and the slowing of closing kinetics of the activation gate upon repolarization affected by drugs of this group.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 8. Physicochemical properties and neurophysiological effects on membrane potentials of crayfish giant axon

The neurophysiological actions of a set of substituted benzyl (1 R)-trans-chrysanthemates and related compounds on the membrane potential of the crayfish giant axon were observed using an intracellular microelectrode. These compounds had one or both of two effects, deceleration of the falling phase of the action potential or elevation of the depolarizing after-potential. The potency of a certain range of compounds to decelerate the rate of the falling phase is mostly determined by the electron-releasing effect of substituents on the aromatic ring. The rate of development of each symptom evaluated in terms of half the time required to reach the maximum response decreased with the hydrophobicity of the compound.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 9. Calcium uptake inhibition in crayfish nerve cord and lobster axon homogenates in vitro by sunthetic pyrethroids

Twenty-five synthetic pyrethroids and related chemicals were assessed for their effects on the uptake of Ca 2+ (as 45Ca 2+) by crude homogenates prepared from crayfish ( Procambarus clarkii) nerve cords and 20 were assessed on the uptake by homogenates prepared from lobster ( Panulirus japonicus) axons. A parabolic relationship was demonstrated between inhibition of Ca 2+ uptake for this series of chemicals and lipophilicity (log P) in both species when tested at 5 μ M. Optimal log P for maximal inhibition was located at about 6.6 and 84(±6)% inhibition was obtained with resmethrin. Compounds of higher or lower log P were either weaker inhibitors, not inhibitors or occasionally resulted in slightly increased levels of Ca 2+ uptake. No direct correlations between the potential for the pyrethroids to inhibit Ca 2+ uptake and the potential for these agents to increase the frequency of spontaneous discharges in crayfish nerve cords, to induce repetitive firing in American cockroaches, or the lethality to cockroaches or to any other neurophysiological or toxicity parameter could be established. It was concluded that although some synthetic pyrethroids are moderately potent inhibitors of Ca 2+ uptake into nerve cord and axonic preparations (i.e., I 50 for trans-resmethrin equals 1 μ M) this inhibition alone does not relate to the neurophysiological changes in isolated nerve preparations or to the toxicity of these agents in insects.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 7. Relationship between induction of repetitive discharges and effects on the action potential

The effects of substituted benzyl (1 R)- trans-chrysanthemates and related compounds on the action potential of the crayfish giant axon were investigated using an intracellular microelectrode. The effects are broadly classified into three types: deceleration of the falling-phase of the action potential (type A), elevation of the depolarizing after-potential (type B), and the combination type (type C). The potency of the type A compounds to decelerate the rate of the falling-phase was determined in terms of the concentration required for reducing the rate to a specified degree. This potency was shown to correlate with the potency to induce repetitive discharges in the cockroach central nerve cord in terms of minimum effective concentration, which was determined previously. The potency of the types B and C compounds to elevate the after-potential was, however, not related directly with the cockroach nerve repetitive activity. The elevation of the after-potential is one of the critical factors but other effects such as a depolarization of the resting potential may be involved in determining the repetitive activity.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 6. Physicochemical properties and the susceptibility to metabolic degradation in American cockroaches

For a series of substituted benzyl chrysanthemates and their dichlorovinyl-sidechain (permethrin) analogs, indices of the in vivo metabolic susceptibility to oxidative and hydrolytic degradation were defined and estimated from insecticidal activities against male adult American cockroaches measured under nonsynergistic and synergistic conditions. Piperonyl butoxide was used as the synergist inhibiting oxidative degradation and NIA 16388 as that against hydrolytic metabolism. Hydrolytic degradability was also experimentally determined in vitro for permethrin analogs using an enzyme preparation from homogenates of the abdominal part of female adult American cockroaches. The effects of substituents of the alcohol moiety on these two types of metabolic parameters were analyzed in terms of physicochemical substituent parameters and regression techniques. Although a number of suggestions on the mechanisms of metabolism were derived from these analyses, the factors determining the in vivo metabolic susceptibility do not always correspond with those participating in the in vitro metabolism. The in vivo metabolic parameter is that comparing the metabolic degradability under conditions in which they exhibit a specified potency of insecticidal activity, differing from the in vitro “absolute” degradability.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 5. Physicochemical substituent factors and neurophysiological effects in knockdown and lethal activities against the house fly

Knockdown and lethal activities of meta- and para-substituted benzyl ( 1R)-trans-chrysanthemates against the house fly were measured under synergistic conditions using piperonyl butoxide as an inhibitor of oxidative metabolism and NIA 16388 as an inhibitor of hydrolytic degradation. The variations in these activities were quantitatively analyzed in terms of physicochemical substituent effects using electronic, hydrophobic, and steric parameters of the aromatic substituents, and regression analysis. The most significant parameter in determining these activities is the steric bulkiness represented by the van der Waals voluem, the effect of which is highly specific to substituent positions. The substituent effects on knockdown and lethal activities against the house fly are shown to correspond well, respectively, with those on the convulsive and lethal activities against the American cockroach. The relationship between these symptomatic activities against the house fly and the neurophysiological activities determined by using excised nerve cords from American cockroaches were also quantitatively analyzed. Each house fly symptomatic activity was found to be analyzable by a linear combination of the neuroexcitatory and neuroblocking activity indices when the transport factor was separated by using the hydrophobicity parameter.

The Mode of Action of Pyrethroids

The comparative mode-of-action as well as quantitative structure-activity studies of pyrethroids were performed at whole insect body and excised nerve preparation levels. Knockdown activity of a set of variously substituted benzyl chrysanthemates and pyrethrates and their related compounds against the house fly was separated into the intrinsic activity and a penetration factor into the target sites. The intrinsic knockdown activity of the compounds was determined under synergistic conditions using inhibitors of oxidative and hydrolytic metabolic activities. The penetration rate constant of the compounds was evaluated from the progress of the knockdown symptom using a first order kinetic model. Symptomatic activities of pyrethroids against the American cockroach and the house fly determined under synergistic conditions were analyzable with such neurophysiological indices as repetitive and neuroblocking activities, which were determined by an extracellular recording technique using the excised central nerve cord of the American cockroach. The repetitive activity of pyrethroids, in turn, was analyzed with the activity to affect the after-potential determined by an intracellular recording method using the giant axon of the crayfish. Activities at whole body and excised nerve levels were shown to be quantitatively analyzable using physicochemical properties of the substituents or molecules by regression analyses.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 4. Physicochemical properties and the rate of progress of the knockdown symptom induced in house flies

A procedure to evaluate the knockdown activity of pyrethroids against house flies in which metabolic factors could be eliminated as far as possible was established. With piperonyl butoxide and NIA 16388 as the inhibitors of oxidative and hydrolytic metabolism, respectively, the “intrinsic” knockdown potencies of 22 substituted benzyl (1 R)- trans-chrysanthemates and related compounds were determined 2.5–3 hr after topical application to house flies. From the intrinsic knockdown potency and the rate of progress of the knockdown symptom from the earliest stage of intoxication, a “penetration” rate constant was estimated by first-order kinetics using a two-compartment model. The rate constant was correlated quantitatively with the hydrophobic parameter of the molecule. The lower the hydrophobicity, the higher the rate constant within the range of compounds used in this study.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 3. Physicochemical substituent effects and the spontaneous neuroexcitatory activity on the crayfish abdominal nerve cords

Neuroexcitatory activity of a series of m- and p-substituted benzyl (1 R)- trans-chrysanthemates was determined using the abdominal nerve cords excised from crayfishes, in terms of the concentration required to increase the spontaneous discharge frequency to a certain value, as well as the rate of the increase of the discharge frequency. The indices for these two types of activity were analyzed quantitatively by means of physicochemical substituent parameters and regression analysis. Being determined most significantly by the steric volume effect, the equineuroexcitatory concentration was found to vary according to the position-specific substituent effects which are very similar to those observed for the neuroexcitatory activity on nerve cords of American cockroaches. The rate of the frequency increase, which is supposed to reflect the rate of penetration into the nerve tissue, was shown to be enhanced by the hydrophilic as well as the electron-withdrawing substituents.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 2. Physicochemical substituent effects and neurophysiological and symptomatic activities against American cockroaches

The substituent effects on the symptomatic and neurophysiological activities of a number of substituted benzyl (1R)-trans-chrysanthemates against American cockroaches were quantitatively analyzed using electronic, hydrophobic, and steric parameters. The effects were shown to be highly specific to substituent positions except for those on the neuroblocking activity. Steric effect of substituents represented by van der Waals volume was found to play the most significant role in determining the variation in each activity. Peculiar substituent effects depending upon the bulkiness and position of substituents, which had been observed in the toxicity of this class of compounds, can be rationalized by the present analysis indicating that the optimum van der Waals volume of substituents is largest at the ortho and smallest at the para position.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 1. Correlations between symptomatic and neurophysiological activities against American cockroaches

A number of substituted benzyl (1R)-trans-chrysanthemates and related compounds were synthesized. Their symptomatic activities in terms of levels which induce convulsions as well as cause death in American cockroaches were determined by injection with and without application of synergists as inhibitors of metabolism. The neuroexcitatory and neuroblocking activities were also determined in terms of minimum effective concentrations to induce repetitive train of impulses and conduction blockage, respectively, to central nerve cords excised from the cockroaches and immersed in Ringer's solution. Correlations between symptomatic and neurophysiological activities were analyzed quantitatively with the aid of molecular hydrophobicity parameter and regression analysis. Each symptomatic activity from which the effect of metabolism is eliminated was found to be analyzable by means of a linear combination of indices for two types of neurophysiological activity when the transport factor is separated by using the hydrophobicity parameter. A closer correlation was found between neuroblocking activity and the “convulsive” effect than between neuroexcitatory activity and the “convulsive” effect, whereas both neurophysiological effects operate together on the cockroaches resulting in paralysis and death.