Ecdysone agonists

Insecticides Acting as Ecdysone Agonists, or Blocking Molting Hormone Activity... 

Diacylhydrazine insecticides (tebufenozide, methoxyfenozide, halofenozide, and chroma-fenozide) act as nonsteroidal ecdysone agonists. They bind to specific ecdysteroid receptorbinding proteins, interrupting the normal sequence of events. Consequently, they induce an incomplete precocious molt, resulting in the mortality of the larva. 

Structure-activity relationship for the activity of non-steroidal ecdysone agonists and the prediction of the ligand binding to the Bombyx mori ecdysone receptors (Y. Nakagawa, Kyoto Univ., Japan)... 

This chapter reviews the structures and biology (physiological, biochemical and molecular basis of mode of action, insect activity spectrum, and eco-toxicological safety) of the commercialized BAH non-steroidal ecdysone agonist insecticides (refer to former reviews on this topic [4—6, 12]). 

Fig. 25.1.1. Chemical structures of 20-hydroxyecdysone (20E 1 R] = OH), the first bisacylhydrazine found to have an ecdysone agonist effect in insect assays (2), and the first bisacylhydrazine (RH-5849 3) well characterized for its ecdysone effects at cellular and whole insect level, as well as binding to Drosophila melanogaster ceW extracts containing ecdysteroid receptor complexes. Numbers on the 20E structure represent the carbon-numbering system.

Several years after the first insecticidal bisacylhydrazine (Fig. 25.1.1 2) was seren-dipitously discovered at the Rohm and Haas Company [9] the first prototype of a bona fide non-steroidal ecdysone agonist bisacylhydrazine, RH-5849 (Fig. 25.1.1 ... 

Table 25.1.1 Commercialized bisacylhydrazine ecdysone agonist insecticides structures, common and coded names and pest spectrum. 

The SAR of the bisacylhydrazines, both during and after the discovery of the commercial compounds, has been extensively studied. This was partly driven by the novelty of the chemistry, mode of action (ecdysone agonists via interaction with the ecdysone receptor), and the availability of suitable assays (tissue, cell and target site based). Numerous papers have been published on this subject and the reader is referred to an excellent review by Dinan and Hormann [6] as a starting point. This section highlights and summarizes the collective findings by various researchers. 

In considering the SAR of bisacylhydrazines for the discovery of new and novel ecdysone agonists, it is essential to understand the SAR of ecdysteroids. This helps to define the three-dimensional (3D) space of ecdysteroids in the EcR LBD and allows for overlaps and comparison with BAH or other ecdysone agonist chemotypes (described below). 

Publication of the crystal structure of the Hdiothis viresence EcR (HvEcR) LBD heterodimerized with LBD of H. viresence ultraspiracle protein (HvUSP) with and without ponasterone A (phytoecdysteroid) or a BAH ecdysone agonist provided a more realistic conformation of the HvEcR LBD and the ligands in the LBD [21]. The most surprising result was that ponasterone A co-crystallized in the HvEcR LBD in an orientation opposite to that predicted by the CoMEA, 4D-QSAR and... 

Fig. 25.1.2. Chemical structure of the first non-steroidal ecdysone agonist compound (RH-5849) with insecticidal activity. Different substitutions on this molecule led to the discovery of the four bisacylhydrazine commercial insecticides. The letters and the numbers refer to substitutions shown in the boxes around the structure.

Elucidation of the crystal stmcture of HvEcR/HvUSP heterodimeric LBDs in the absence or presence of steroidal or non-steroidal ligands [21] conclusively demonstrated the binding of BAH in the EcR LBD. These results also made it possible to verify the pharmacophore stmctural requirements for both an ecdyste-roid (ponasterone A) and a non-steroidal ecdysone agonist BAH (BY106830) interaction with residues specifically in a lepidopteran EcR LBD (Fig. 25.1.3A and 3B,... 

Other Chemistries and Potential for New Ecdysone Agonist Insecticides... 

Conclusions and Future Prospects of Ecdysone Agonist Chemistries... 

TBW larvae characterized by rapid feeding cessation and absence of tarry frass (as seen with the IDDs), with the cuticle not impaired. This unique phenotype was not similar to that produced by juvenile hormone agonists, ecdysone agonists or the chitin biosynthesis disruptor classes represented by the BPUs. 

Measurement of Receptor-Binding Activity of Non-Steroidal Ecdysone Agonists Using in vitro Expressed Receptor Proteins (EcR/USP Complex) of Chilo suppressalis and Drosophila melanogaster... 

Figure 1. Structures of ecdysteroids (I) and non-steroidal ecdysone agonists (II, HI).

Table 1. Binding activities (pICso values) of ecdysone agonists against in vitro transcribed-transiated EcR-BlAJSP... 

As stated above, it is well known that the insecticidal activity of most nonsteroidal ecdysone agonists is higher to Lepidoptera than to Diptera. Using in vitro expressed EcR/USP complex and cellular extracts, Dhadialla et al. showed... 

Figure 4. Relationship of receptor-binding activities (pICso) between C. suppressalis and D. melanogaster. Solid circles, ecdysteroids. Open circles, non-steroidal ecdysone agonists.

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