Change the channel: CysLoop receptor antagonists from nature

Abstract

Vertebrate and invertebrate ligand‐gated ion channels (LGICs) exhibit significant structural homology and often share ligands. As a result, ligands with activity against one class can be brought to bear against another, including for development as insecticides. Receptor selectivity, metabolism and distribution must then be optimized using chemical synthesis. Here we review natural products (NPs) that ligate and inhibit the Cys‐loop family of LGICs, which benefit from the unique physicochemical properties of natural product space but often present a high synthetic burden. Recent advances in chemical synthesis, however, have opened practical entries into these complex structures, several of which are highlighted. © 2020 Society of Chemical Industry

Structure Simplification of Natural Products as a Lead Generation Approach in Agrochemical Discovery

“…190 Although the total synthesis of nodulisporic acid analogs has been an area of ongoing interest, 191 simplified synthetic derivatives of nodulisporic acid do not appear to have been explored, which was likely influenced by the complex structure. Importantly, however, the MoA of nodulisporic acid is a binding site in the glutamategated chloride channel that may overlap with that of the avermectins in insects but not mammals, 192,193 a characteristic also shared by another class of insecticidal indole alkaloids, the okaramines. 194 Thus nodulisporic acid and related classes of NPs (e.g., shearinines, okaramines) represent potential models for simplified synthetic mimics.…”

Picrotoxane sesquiterpenoids: chemistry, chemo- and bio-syntheses and biological activities

“…In invertebrates, CysLoop receptors include GABARs, nAChRs, and glutamate-gated chloride channels (GluCls). 216 5.2.1 Antagonistic action against GABA receptors. Early studies reported the antagonistic effect of picrotoxin on gaminobutyric acid (GABA), a major inhibitory neurotransmitter.…”

“…In invertebrates, CysLoop receptors include GABARs, nAChRs, and glutamate-gated chloride channels (GluCls). 216…”

Understanding the biological action of insecticides is the key to their continuous improvement

“…Shenvi, Tong, and Baker reviewed ligand gated ion channels and discuss how understanding of their commonalities can be leveraged toward insecticide discovery 4 . Natural product ligands of the cys‐loop family of these channels provide insight into binding mechanisms which can guide efforts to target them with a synthetic approach.…”