Ion channels and receptor as targets for the control of parasitic nematodes

Abstract

Many of the anthelmintic drugs in use today act on the nematode nervous system. Ion channel targets have some obvious advantages. They tend to act quickly, which means that they will clear many infections rapidly. They produce very obvious effects on the worms, typically paralyzing them, and these effects are suitable for use in rapid and high-throughput assays. Many of the ion channels and enzymes targeted can also be incorporated into such assays. The macrocyclic lactones bind to an allosteric site on glutamate-gated chloride channels, either directly activating the channel or enhancing the effect of the normal agonist, glutamate. Many old and new anthelmintics, including tribendimidine and the amino-acetonitrile derivatives, act as agonists at nicotinic acetylcholine receptors; derquantel is an antagonist at these receptors. Nematodes express many different types of nicotinic receptor and this diversity means that they are likely to remain important targets for the foreseeable future. Emodepside may have multiple effects, affecting both a potassium channel and a pre-synaptic G protein-coupled receptor; although few other current drugs act at such targets, this example indicates that they may be more important in the future. The nematode nervous system contains many other ion channels and receptors that have not so far been exploited in worm control but which should be explored in the development of effective new compounds.

Novel GABA receptor pesticide targets

“…[ 3 H]Ave binding in Musca is not inhibited by GABA, fipronil or cyclodienes but is by flu. The C. elegans glutamategated chloride channel was important in structural definition of the RDL AVE site although a muscle glutamate receptor may be involved in contributing to or the cause of the toxicity [69][70][71][72][73][74][75]. Decreased binding is conferred by in silico mutations to A/Q6 and B1/S58 [75].…”

Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans

“…Further genes, regulating membrane permeability (osm-1) and gap junctions (unc-7 and unc-9), are also involved (Dent et al, 2000). Defining the role of GluCl mutations in conferring ivermectin resistance to parasitic nematodes in the field is a less tractable and more controversial problem (Wolstenholme et al, 2004).…”

Effectiveness of Ivermectin and Albendazole Against Ostertagia on Sheep in Bogor, Indonesia

“…Ivermectin (IVM), anggota antihelminth dari kelas makrosiklik lakton, berspektrum luas dalam melawan nematoda gastrointestinal dan ektoparasit (Campbell et al 1983). Mekanisme IVM adalah melepaskan dan mengikat α subu it sebagai reseptor glutamate-gated chloride channels (GluCl) di sinapsis saraf tertentu (Wolstenholme 2011) yang menghambat proses memakan, fekunditas, dan motilitas nematoda (Yates et al 2003). Albendazole (ABZ) merupakan salah satu anggota dari kelas BZD dengan senyawa metil karbamat yang efektif melawan nematoda gastrointestinal, cacing pita, dan cacing hati (Campbell 1990).…”

“…Albendazole (ABZ) merupakan salah satu anggota dari kelas BZD dengan senyawa metil karbamat yang efektif melawan nematoda gastrointestinal, cacing pita, dan cacing hati (Campbell 1990). Mekanisme ABZ adalah mengikat dengan afinitas tinggi β-tubulin yang menghambat dimerisasi dengan α-tubulin dalam pembentukan mikrotubulus pada sel nematoda (Wolstenholme 2011).…”