Indoxacarb, metaflumizone, and other sodium channel inhibitor insecticides: Mechanism and site of action on mammalian voltage-gated sodium channels

Abstract

Sodium channel inhibitor (SCI) insecticides were discovered almost four decades ago but have only recently yielded important commercial products (eg., indoxacarb and metaflumizone). SCI insecticides inhibit sodium channel function by binding selectively to slow-inactivated (non-conducting) sodium channel states. Characterization of the action of SCI insecticides on mammalian sodium channels using both biochemical and electrophysiological approaches demonstrates that they bind at or near a drug receptor site, the "local anesthetic (LA) receptor." This mechanism and site of action on sodium channels differentiates SCI insecticides from other insecticidal agents that act on sodium channels. However, SCI insecticides share a common mode of action with drugs currently under investigation as anticonvulsants and treatments for neuropathic pain. In this paper we summarize the development of the SCI insecticide class and the evidence that this structurally diverse group of compounds have a common mode of action on sodium channels. We then review research that has used site-directed mutagenesis and heterologous expression of cloned mammalian sodium channels in Xenopus laevis oocytes to further elucidate the site and mechanism of action of SCI insecticides. The results of these studies provide new insight into the mechanism of action of SCI insecticides on voltage-gated sodium channels, the location of the SCI insecticide receptor, and its relationship to the LA receptor that binds therapeutic SCI agents.

The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides

“…(Table 1). These facts indicate that SCBI receptors in the Na v 1.4 and BgNa v 1-1a channels are not identical (2). In our models, SCBIs would be attracted to big hydrophobic residues F 3p44 and L 4i8 in BgNa v 1-1a more strongly than to their smaller cognates L 3p44 and C 4i8 in rNa v 1.4 (Table 4).…”

“…Unlike other SCBIs, MFZ can bind to the resting sodium channels (2). The long predicted hydrophobic access pathway for LAs in the closed sodium channels (25) was first visualized in homology models of sodium channels where LAs are proposed to reach the closed sodium channels through the "sidewalk" in the III/IV repeat interface (21,32).…”

“…1), are among the relatively new classes of insecticides with favorable selectivity (1)(2)(3). The selective toxicity of indoxacarb is due to insect-specific metabolism that decarboxylates indoxacarb to produce a more toxic derivative, DCJW (3).…”

Mode of Action of Plant-Derived Natural Insecticides

“…In the nervous system, there are two types of voltage-gated channels that contribute to the action potential, namely, the sodium and potassium channels. It is believed that DDT and pyrethroid insecticides act on sodium channels, which causes a delay in sodium channel closing, resulting in excessive neuroexcitation, fi nally leading to loss of control of the coordinated movement, paralysis, and death (Matsumura 1985 ;Bloomquist 1999 ;Nauen 2006 ;Du et al 2013 ;Von Stein et al 2013 ).…”

Molecular Mechanism of Action and Selectivity of Sodium Ch annel Blocker Insecticides

“…Metaflumizone, like indoxacarb, is highly insecticidal with low mammalian toxicity [22–24]. For a more in-depth review of the history of this class of insecticides, please see several recently published reviews [2, 16, 18, 21, 22, 25–27]. …”