Endogenous protein and enzyme fragments induce immunoglobulin E-independent activation of mast cells via a G protein-coupled receptor, MRGPRX2.

Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through 2 main pathways, immunoglobulin E-dependent and E-independent activation. In the latter pathway, mast cells are activated by a diverse range of basic molecules (collectively known as basic secretagogues) through Mas-related G protein-coupled receptors (MRGPRs). In addition to the known basic secretagogues, here, we discovered several endogenous protein and enzyme fragments (such as chaperonin-10 fragment) that act as bioactive peptides and induce immunoglobulin E-independent mast cell activation via MRGPRX2 (previously known as MrgX2), leading to the degranulation of mast cells. We discuss the possibility that MRGPRX2 responds various as-yet-unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells.

Quantitative analysis of electron transport inhibition of rat-liver mitochondrial cytochrome bc1 complex by nitrophenols.

A series of nitrophenolic electron transport inhibitors (2-sec-butyl-4-nitro-6-substituted phenols and 2-sec-butyl-4-substituted-6-nitrophenols) of rat-liver mitochondrial cytochrome bc1 complex (cyt. bc1 complex) was synthesized. To obtain information on the three-dimensional structure of the ubiquinone redox site of cyt. bc1 complex, the structure-inhibitory activity relationship was examined by regression analysis using physiocochemical substituent parameters. The inhibitory activity increased as the hydrophobicity and the electron-withdrawing ability of the 4- and 6-substituents increased. These results indicated that hydrophobic interaction between the inhibitor molecule and the binding domain should be important and that an anionic form of nitrophenols may be the active form at the binding domain. Hydrogen-bond-acceptable 4-substituents such as methoxy and nitro groups, but not cyano group, were favorable to the inhibitory activity. This result, along with the fact that phenolic OH group was essential for the activity, suggested that nitrophenols occupy the ubiquinone redox site by forming two hydrogen-bond bridges as proposed for natural ubiquinone binding. Although a cyano group is hydrogen-bond-acceptable, hydrogen-bond formation between the 4-cyano group and the binding domain was not suggested. This result and molecular orbital calculation studies on electrostatic potential of the inhibitors suggested that hydrogen-bond donating residue may not be located in the region where the rod-like cyano (C identical to N) bond directs.

Origin of selective inhibition of mitochondrial complex I by pyridinium-type inhibitor MP-24.

Positively charged pyridiniums are unique inhibitors to probe the structural and functional properties of the ubiquinone reduction site of bovine heart mitochondrial complex I. In this study, we synthesized a series of neutral as well as pyridinium analogues of MP-24 (N-methyl-4-[2-methyl-2-(p-tert-butylbenzyl)propyl]pyridinium), a selective inhibitor of one of the two proposed binding sites of these pyridinium-type inhibitors of complex I (H. Miyoshi et al., J. Biol. Chem. 273 (1998) 17368-17374), to elucidate the origin of its selectivity. Inhibitory potencies of all neutral and pyridinium analogues with tetraphenylboron (TPB(-)), which forms an ion-pair with pyridiniums, were comparable, although the degrees of selective inhibition by pyridiniums without TPB(-) were entirely different. In contrast to MP-24, the dose-response curves of nonselective pyridiniums and all neutral analogues were not affected by incubation conditions. These results strongly suggested that the process of the inhibitor passage to the binding sites is responsible for the selective inhibition.

Comparison of the inhibitory action of synthetic capsaicin analogues with various NADH-ubiquinone oxidoreductases.

Capsaicin is a new naturally occurring inhibitor of proton-pumping NADH-ubiquinone oxidoreductase (NDH-1), that competitively acts against ubiquinone. A series of capsaicin analogues was synthesized to examine the structural factors required for the inhibitory action and to probe the structural property of the ubiquinone catalytic site of various NADH-ubiquinone reductases, including non-proton-pumping enzyme (NDH-2), from bovine heart mitochondria, potato tuber (Solanum tuberosum, L) mitochondria and Escherichia coli (GR 19N) plasma membranes. Some synthetic capsaicins were fairly potent inhibitors of each of the three NDH-1 compared with the potent rotenone and piericidin A. Synthetic capsaicin analogues inhibited all three NDH-1 activities in a competitive manner against an exogenous quinone. The modification both of the substitution pattern and of the number of methoxy groups on the benzene ring, which may be superimposable on the quinone ring of ubiquinone, did not drastically affect the inhibitory potency. In addition, alteration of the position of dipolar amide bond unit in the molecule and chemical modifications of this unit did not change the inhibitory potency, particularly with bovine heart and potato tuber NDH-1. These results might be explained assuming that the ubiquinone catalytic site of NDH-1 is spacious enough to accommodate a variety of structurally different capsaicin analogues in a dissimilar manner. Regarding the moiety corresponding to the alkyl side chain, a rigid diphenyl ether structure was more inhibitory than a flexible alkyl chain. Structure-activity studies and molecular orbital calculations suggested that a bent form is the active conformation of capsaicin analogues. On the other hand, poor correlations between the inhibitory potencies determined with the three NDH-1 suggested that the structural similarity of the ubiquinone catalytic sites of these enzymes is rather poor. The sensitivity to the inhibition by synthetic capsaicins remarkably differed between NDH-1 and NDH-2, supporting the notion that the sensitivity against capsaicin inhibition correlates well with the presence of an energy coupling site in the enzyme (Yagi, T. (1990) Arch. Biochem. Biophys. 281, 305-311). It is noteworthy that several synthetic capsaicins discriminated between NDH-1 and NDH-2 much better than natural capsaicin.

Interaction between neutrophil-derived elastase and reactive oxygen species in cartilage degradation.

The role of proteases and reactive oxygen species (ROS) in polymorphonuclear neutrophil (PMN) induced cartilage degradation in vitro were studied. ONO-5046, a novel synthetic elastase inhibitor, significantly and dose dependently protected cartilage from degradation induced by PMNs stimulated with phorbol myristate acetate (PMA), opsonized zymosan, N-formyl-methionyl-leucyl-phenylalanine plus cytochalasin-B, or A-23187. The degradation by PMA-stimulated PMNs was unaffected by protease inhibitors which lack anti-elastase activity. However, the hydrogen peroxide (H2O2) reducing agent catalase afforded significant protection. Measurement of elastase activity following PMN activation by PMA showed that antioxidants which reduce H2O2 and/or hypochlorous acid decreased elastase activity. Thus, it is suggested that an indirect interaction between ROS and elastase activity may exist in PMN induced cartilage degradation. Furthermore, the possible implication of an endogenous elastase inhibitor(s) is discussed.

Inhibition of electron transport of rat-liver mitochondria by synthesized antimycin A analogs.

A series of antimycin A analogs was synthesized by replacement of a dilactone-ring moiety of natural antimycin A by various alkyl, substituted phenyl, substituted diphenyl ether, or amino acid ester groups. The structure-inhibitory activity relationship was studied with rat-liver mitochondria to identify roles of the dilactone-ring moiety in the inhibitor binding to a Qi reaction center of cytochrome bc1 complex. All derivatives caused further reduction of cytochrome b reduced by succinate and the oxidant-induced reduction, showing that the derivatives inhibited electron transport by interacting with a Qi reaction center. The inhibition tended to increase as the hydrophobicity of the inhibitor increased. The mode of binding of inhibitor molecules to a Qi center, which was reflected in, for example, a sigmoidal titration curve for respiratory inhibition and a time-dependent change in inhibitory activity, varied depending on structure. These results suggested that the role of the dilactone-ring moiety of antimycin A may be not only to support hydrophobic interaction with the binding domain by increasing the hydrophobicity of the molecule, as proposed earlier, but also to regulate close fitting of the salicylic acid moiety to the binding domain.

Structural factors of rotenone required for inhibition of various NADH-ubiquinone oxidoreductases.

We performed a structure-activity study of a series of synthetic rotenone analogues to elucidate the structural factors of rotenone required for inhibition and to probe the structural properties of the rotenone binding site of various NADH-ubiquinone oxidoreductases (NDH), including both proton-pumping (NDH-1) and non-proton-pumping (NDH-2) enzymes, from bovine heart mitochondria, potato tuber (Solanum tuberosum L.) mitochondria and Escherichia coli (GR 19N) plasma membranes. Using a benzyloxy group as a substitute for the E-ring moiety of natural rotenone, systematically selected structural modifications of the A-ring became feasible. The inhibitory potency of bovine NDH markedly varied depending upon structural modifications of the A-ring. The native chemical structure (2,3-dimethoxy substitution) appeared to be the most favorable for the activity. The spatial location of the hydrogen-bond acceptable methoxy oxygens may be important for tight fitting into the binding site. However, replacing one of the two methoxy groups by an ethoxy group almost completely retained the activity, indicating that the binding environment of the A-ring moiety is spacious enough to accommodate a substituent larger than the methoxy group. The manner of action of the derivative lacking the 12-C = O group in the C-ring differed from that of natural rotenone, indicating that this functional group is important for supporting the inhibitory action of natural rotenone itself. Regarding potato tube and E. coli NDH-1, the sensitivity of the two enzymes to the inhibition by rotenone analogues was much lower than that of the bovine enzyme. The 2,3-dimethoxy substitution was the most favorable for the activity with potato NDH-1, whereas this substitution pattern was not necessarily the best with E. coli NDH-1. A rule governing inhibitory potency depending upon structural modifications was ambiguous for the two enzymes because of a small variation in the inhibitory potencies. These findings indicated that the local binding environment of the A-ring moiety of rotenone in bovine NDH is specific and differs considerably from that in potato and E. coli NDH-1.

Structural factors of antimycin A molecule required for inhibitory action.

A series of antimycin A analogues was synthesized by modifying the salicylic acid moiety, whereas the portion of the molecule corresponding to the natural dilactone-ring moiety was fixed as di-n-octyl L-glutamate. To probe the structure of the antimycin A binding site, the structural factors of the salicylic acid moiety required for inhibitory action were examined by means of structure-activity studies with intact rat-liver mitochondria and the cytochrome bc1 complex isolated from bovine heart mitochondria. As suggested earlier (Rieske, J.S. (1976) Biochim. Biophys. Acta 456, 195-247), the phenolic OH was very important for inhibition. For the derivatives which do not possess a formylamino group in the 3-position (ortho to the phenolic OH), the inhibitory activity tended to increase as the electron-withdrawing property of the substituent increased, i.e., as the acidity of the phenolic OH group increased. This indicates that the acidity of the phenolic OH is an important factor governing inhibition. While the electron-withdrawing property of the formylamino group itself is rather poor, 3-formylamino derivatives elicited potent activity. The conformation of the 3-formylamino group was also found to be a very important factor in establishing inhibitory activity. In addition, the bulkier the moiety corresponding to the 3-formylamino group, the lower the activity. These results demonstrate that the presence of the 3-formylamino group, and its proper conformation, are needed for a close fitting of antimycin A to its binding domain. Although the inhibitors that lack a 3-formylamino group retained fairly potent activity, their effects on the reduction of cytochromes b and c1 were somewhat different from those of natural antimycin A, indicating that the 3-formylamino group is essential for inhibitor binding to the cytochrome bc1 complex in the same manner as natural antimycin A. It is concluded that both the 3-formylamino group and the phenolic OH of antimycin A make important contributions to specific interactions with the amino acid residues of the cytochrome b.

Definition of crucial structural factors of acetogenins, potent inhibitors of mitochondrial complex I.

Some natural acetogenins are the most potent inhibitors of bovine heart mitochondrial complex I. These compounds are characterized by two functional units (i.e. hydroxylated tetrahydrofuran (THF) and alpha,beta-unsaturated gamma-lactone ring moieties) separated by a long alkyl spacer. To elucidate which structural factors of acetogenins including their active conformation are crucial for the potent inhibitory effect, we synthesized a series of novel acetogenin analogues possessing bis-THF rings. The present study clearly demonstrated that the natural gamma-lactone ring is not crucial for the potent inhibition, although this moiety is the most common structural unit among a large number of natural acetogenins and has been suggested to be the only reactive species that directly interacts with the enzyme (Shimada et al., Biochemistry 37 (1998) 854-866). The presence of free hydroxy group(s) in the adjacent bis-THF rings was favorable, but not essential, for the potent activity. This was probably because high polarity (or hydrophilicity), rather than hydrogen bond-donating ability, around the bis-THF rings is required to retain the inhibitor in the active conformation. Interestingly, length of the alkyl spacer proved to be a very important structural factor for the potent activity, the optimal length being approximately 13 carbon atoms. The present study provided further strong evidence for the previous proposal (Kuwabara et al., Eur. J. Biochem. 267 (2000) 2538-2546) that the gamma-lactone and THF ring moieties act in a cooperative manner on complex I with the support of some specific conformation of the spacer.

A model of antimycin A binding based on structure-activity studies of synthetic antimycin A analogues.

The structural factors of antimycin A molecule required for inhibitory action were studied using newly synthesized antimycin A derivatives with bovine heart submitochondrial particles, in order to probe the interaction between antimycin A and its binding site. In particular, we focused upon the roles of the amide bond bridge, which connects the salicylic acid and dilactone ring moieties, and the 3-formylamino group in the salicylic acid moiety. The lack of formation of an intramolecular hydrogen-bond between phenolic OH and amide carbonyl groups resulted in a remarkable loss of the activity (by four orders of magnitude), indicating that this hydrogen-bond is essential for the inhibition. This result suggested that both the phenolic OH and the carbonyl groups form a hydrogen-bond with some residues at a fixed conformation. In addition, the inhibitory potency was remarkably decreased by N-methylation of the amide bond moiety, indicating that the NH group might function in hydrogen-bond interaction with the binding site. The N-methylation of 3-formylamino group also resulted in a decrease in the activity, probably due to a loss of the rotational freedom of this functional group. Molecular orbital calculation studies with respect to the conformation of the 3-formylamino group indicated that this group takes an active conformation when the formyl carbonyl projects to the opposite side of the phenolic OH group. Based upon a series of structure-activity studies of synthetic antimycin A analogues, we propose a tentative model for antimycin A binding in its binding cavity.

Topographical characterization of the ubiquinone reduction site of glucose dehydrogenase in Escherichia coli using depth-dependent fluorescent inhibitors.

Membrane-bound glucose dehydrogenase in Escherichia coli possesses a binding site for ubiquinone as well as glucose, metal ion and pyrroloquinoline quinone. To probe the depth of the ubiquinone binding site in the membrane environment, we synthesized two types of fluorenyl fatty acids which bear an inhibitor mimic moiety (i.e., specific inhibitor capsaicin) close to the fluorene located at different positions in the alkyl tail chain; one close to the polar carbonyl head group (alpha-(3, 4-dimethoxyphenyl)acetyloxy-7-nonyl-2-fluoreneacetic acid, alpha-DFA), and the other in the middle of the chain (theta-(3, 4-dimethoxyphenyl)acetyloxy-7-ethyl-2-fluorenenonanoic acid, theta-DFA). Mixed lipid vesicles consisting of phosphatidylcholine (PC) and alpha-DFA or theta-DFA were prepared by sonication method, and fluorescent quenching against a hydrophilic quencher, iodide anion, was examined. The vesicles containing alpha-DFA were more susceptible to quenching than those containing theta-DFA, indicating that the fluorene and consequently capsaicin mimic moiety are located at different depths in the lipid bilayer depending upon the position of attachment to the alkyl tail chain. The purified glucose dehydrogenase was reconstituted into PC vesicles which consisted of PC and alpha-DFA or theta-DFA with various molar ratios. For both types of reconstituted vesicles, the extent of inhibition of short-chain ubiquinone reduction activity increased with increases in the molar ratio of fluorenyl fatty acid to PC. The ubiquinone reduction activity was more significantly inhibited in the reconstituted vesicles containing alpha-DFA compared to those containing theta-DFA. Our findings strongly suggested that the ubiquinone reduction site in glucose dehydrogenase is located close to the membrane surface rather than in the hydrophobic membrane interior.

Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I.

The annonaceous acetogenins are the most potent of the known inhibitors of bovine heart mitochondrial complex I. These inhibitors act, at the terminal electron transfer step of the enzyme, in a similar way to the usual complex I inhibitors, such as piericidin A and rotenone; however, structural similarities are not apparent between the acetogenins and these known complex I inhibitors. A systematic set of isolated natural acetogenins was prepared and examined for their inhibitory actions with bovine heart mitochondrial complex I to identify the essential structural factors of these inhibitors for the exhibition of potent activity. Despite their very potent activity, the structural requirements of the acetogenins are not particularly rigid and remain somewhat ambiguous. The most common structural units, such as adjacent bis-tetrahydrofuran (THF) rings and hydroxyl groups in the 4- and/or 10-positions, were not essential for exhibiting potent activity. The stereochemistry surrounding the THF rings, surprisingly, seemed to be unimportant, which was corroborated by an exhaustive conformational space search analysis, indicating that the model compounds, with different stereochemical arrangements around the THF moieties, were in fairly good superimposition. Proper length and flexibility of the alkyl spacer moiety, which links the THF and the alpha, beta-unsaturated gamma-lactone ring moieties, were essential for the potent activity. This probably results from some sort of specific conformation of the spacer moiety which regulates the two ring moieties to locate into an optimal spatial position on the enzyme. It is, therefore, suggested that the structural specificity of the acetogenins, required for optimum inhibition, differs significantly from that of the common complex I inhibitors in which essential structural units are compactly arranged and conveniently defined. The structure-activity profile for complex I inhibition is discussed in comparison with those for other biological activities.

Inhibition of electron transport of rat liver mitochondria by unnatural (-)-antimycin A3.

The inhibition of electron transport by unnatural (-)-antimycin A3 was examined with rat liver mitochondria and compared with that of natural (+)-antimycin A3. (-)-Antimycin A3 inhibited respiration about 1/100th as strongly as natural (+)-antimycin A3. (-)-Antimycin A3 binding to the cytochrome bc1 complex did not seem to induce a conformational change in this proteinous complex. The binding site of (-)-antimycin A3 was probably the same as that of (+)-antimycin A3 (at the Qi center). However, the mode of interaction with the Qi center by (-)-antimycin A3 and (+)-antimycin A3 was somewhat different.

Structure--taste relationship of perillartine and nitro- and cyanoaniline derivatives.

The relationship between structure and taste potency of perillartine and its analogues was investigated quantitatively by physicochemical parameters and regression analysis. The results indicated that the hydrophobicity estimated from the 1-octanol/water partition coefficient and the molecular widths from the bond axis connecting the oxime carbon and alicyclic ring are important, regardless of whether the taste is sweet or bitter, so far as the taste potency is concerned. The SAR for the sweet/bitter ratio was not established quantitatively, but the molecular width and thickness and the position-specific electronic effect seem to delineate the ratio qualitatively; i.e., in principle, the wider and/or the thicker the molecule, the more bitter the taste. Comparatively, the QSAR of 5-nitro- and 5-cyanoaniline sweetners was formulated to show the insignificance of the hydrophobicity within the compounds investigated but the importance of the steric dimensions in determining the activity.

Structure--sweetness relationship of L-aspartyl dipeptide analogues. A receptor site topology.

The relationship between structure and the sweet potency of L-aspartyl dipeptide analogues was investigated by physicochemical parameters and regression analysis. The dipeptide analogues reported were divided into the following four classes: L-aspartic acid amides, L-aspartylaminoethyl esters, L-aspartylaminopropionates, and L-aspartyl-aminoacetates. The analysis carried out for each class indicated that the electron-withdrawing effect of the substituents directed to the peptide bond and the steric dimensions of the molecules are important in eliciting the sweet taste. The values of coefficients of the electronic sigma terms in the correlations for L-aspartic acid amides, L-aspartylaminoethyl esters, and L-aspartylaminopropionates were approximately 0.7, indicating a common basic site on the receptor surface. The value for L-aspartylaminoacetates was approximately 1.5, and this value suggests, together with the factor of the participation of steric parameters, a closer or geometrically more proper fit to the receptor, explaining the generally higher potency of this class compared to the other three. The receptor model drawn based on these quantitative analyses appears to be consistent with other classes of sweeteners of apparently unrelated structures.

Quantitative structure-activity relationship of insect juvenile hormone mimetic compounds.

Juvenile hormone mimetic activities on Aedes aegypti (yellow-fever mosquito) and Tenebrio molitor (yellow mealworm) of compounds having (2E,4E)-3,7,11-trimethyl-2,4-dodecadienone structures were comparatively and quantitatively analyzed in terms of their physiochemical structural parameters and by regression analysis. They were structurally composed of three classes, ester and thiol ester derivatives, amides, and ketones, depending on the C1 substituents. The results indicated that the steric dimensions and the hydrophobicity of the whole molecule are important factors in governing the activity through these classes as well as through both insect species. The effects of the structure of the C1 and C11 substituents, the two ends of the chain molecule, are specific to the insect. The length along the bond axis of the C1 substituents is significant and the hydroxy and alkoxy functions attached to the C11 atom favor the activity on A. aegypti, whereas with T. molitor the width of the C1 substituents in the direction perpendicular to the bond axis is significant and the position-specific hydrophobicity of the C1 moiety enhances the activity. The activity is also affected differently by the compound types. The amide and ketone series of compounds are more active than the corresponding ester type of compounds on T. molitor, while the favorable types on A. aegypti are the ester and ketone derivatives. Correlation equations formulated for 85 active compounds on A. aegypti and 84 compounds on T. molitor led us to draw a hypothetical "mode of action" model for each species, which visualizes the overall similarity as well as the species differences of the interaction site or the receptor and may show the structural conditions necessary for activity.

Quantitative aspects of the receptor binding of cytokinin agonists and antagonists.

Congeneric 4-anilino- and 4-(alkylamino)-2-methylpyrrolo[2,3-d]pyrimidines showed cytokinin and anticytokinin activities, depending on the structure of their 4-substituents, and the antagonistic nature of the latter was established kinetically. The effect of the substituent on these activities was analyzed quantitatively by using physicochemical parameters and regression analysis to give a single, common equation for both the agonists and antagonists. The results indicated that the maximum width of the N4 substituents is an important factor both for binding to the receptor, thus the extent of activity, and for the quality of activity, agonistic or antagonistic. The electron-withdrawing effect and hydrophobicity of the substituents further enhance binding and, thus, activity, irrespective of the quality of the activity. These results coincide with and/or provide evidence for the hypothesis that in hormonal action, agonist binding causes a conformational change of an otherwise inactive receptor to the active form and that antagonists are species that bind similarly to the receptor but do not cause the effective conformational change.

Quantitative structure-activity relationships of the bitter thresholds of amino acids, peptides, and their derivatives.

Bitter thresholds of a total of 93 amino acids, peptides, and their derivatives were analyzed quantitatively by use of hydrophobicity parameters reported for amino acid side chains and those for the whole molecules estimated from partition coefficients obtained experimentally. We also explored the steric parameters that best explained the variation in the intensity of bitterness attributable to the molecular shape. The results showed that the total length along the zigzag peptide backbone chain of the molecule is an important factor. The bitterness of nonzwitterionic N-acyl and ester derivatives and that of neutral N-acyl ester derivatives were expressed by a single, common equation together with those of zwitterionic amino acids and peptides. Thus the interaction via the charge with the receptor site was probably not an indispensible factor for triggering of the bitter sensation. This study, together with earlier ones, may serve as a prototype of approaches toward unraveling structure-activity relationships of complex molecules like amino acids, peptides, and their derivatives that are of medicinal or agricultural importance.

Quantitative structure-activity relationships in cytokinin agonistic and antagonistic pyrido[2,3-d]pyrimidine derivatives: insights into receptor topology.

2-(Methylthio)pyrido[2,3-d]pyrimidines having various alkylamino and anilino substituents at the 4-position were prepared and tested for their cytokinin agonistic and antagonistic activities by the tobacco callus bioassay. The alkyl series of compounds showed anticytokinin activity, whereas the anilino derivatives exhibited both cytokinin and anticytokinin activities depending on the structure and position of the benzene substituents. Quantitative structure-activity analyses were carried out for each class and for the combined set of compounds with use of physicochemical parameters and regression analysis, indicating that the quality of activity, agonistic or antagonistic, as well as the extent of activity, is significantly affected by the steric features of the molecule. On the basis of the present results and previous quantitative analyses on cytokinins and other classes of anticytokinins, a dimensional map for the cytokinin receptor site can be drawn, which can serve as the basis for the design of novel agonists and antagonists.

Quantitative structure-activity relationships of insecticides and plant growth regulators: comparative studies toward understanding the molecular mechanism of action.

Emphasis was put on the comparative quantitative structure-activity approaches to the exploration of action mechanisms of structurally different classes of compounds showing the same type of activity as well as those of the same type of compounds having different actions. Examples were selected from studies performed on insecticides and plant growth regulators, i.e., neurotoxic carbamates, phosphates, pyrethroids and DDT analogs, insect juvenile hormone mimics, and cytokinin agonistic and antagonistic compounds. Similarities and dissimilarities in structures required to elicit activity between compounds classes were revealed in terms of physicochemical parameters, provoking further exploration and evoking insights into the molecular mechanisms of action which may lead to the development of new structures having better qualities.