A NONPEPTIDAL PEPTIDOMIMETIC AGONIST OF THE INSECT FLRFAMIDE MYOSUPPRESSIN FAMILY

Benzethonium chloride (Bztc) is the first totally nonpeptide ligand fo r an insect, indeed an invertebrate, peptide receptor. Bztc mimics the inhibitory physiological activity of the myosuppressins, a subfamily of the FLRFamides, in three different insect bioassay systems. The inh ibitory action of leucomyosuppressin and the nonpeptide Bztc in both t he cockroach hindgut and the mealworm neuromuscular junction can be bl ocked by the lipoxygenase inhibitor, nordihydroguaiaretic acid, provid ing evidence for similar modes of action. Lipoxygenase metabolites of arachidonic acid may mediate inhibition of neuromuscular transmission by these two factors. In addition, Bztc competitively displaces a radi olabeled myosuppressin analogue from high- and low-affinity receptors of the locust oviduct. Thus, the nonpeptide interacts with both bindin g and activating regions of myosuppressin receptors. Molecular dynamic s experiments in which selected functional groups of Bztc were fit ont o corresponding functional groups of low-energy myosuppressin pentapep tide structures indicate how Bztc may mimic the myosuppressins at a mo lecular level. The discovery of Bztc as a nonpeptidal peptidomimetic a nalogue provides an opportunity to develop new pest management strateg ies by targeting an insect's own peptide receptor.