Emodepside is synthesised by attaching a morpholine ring “at the paraposition of each of the two D-phenyllactic acids” to PF1022A, a metabolite of Mycelia sterile, a fungus that inhabits the leaves of Camellia japonica – a flowering shrub.
Anthelmintic effects
When applied to nematodes, emodepside has been shown to have a range of effects, inhibiting muscle in the parasitic nematodeAscaris sum and inhibiting locomotive and pharyngeal movement in Caenorhabditis elegans in addition to having effects in other tissues such as the inhibition of egg laying.
Mechanism of action
One of the ways in which this drug achieves its effects has been shown to be through binding to a group of G-protein coupled receptors called latrophilins, first identified as being target proteins for α-latrotoxin, a component of black widow spider venom that can cause paralysis and subsequent death in nematodes and humans alike. LAT-1 and LAT-2 are located presynaptically at the neuromuscular junction in Caenorhabditis elegans and share 21% amino acid identity with each other. Following receptor-ligand binding, a conformational change induced in the receptor activates the Gq protein, freeing the Gqα subunit from the βγ complex. The Gqα protein then goes on to couple-to and activate the signaling molecule phospholipase-C-β, a protein that has been identified as being key to the modulation of regulatory pathways of vesicle release in C.elegans. In its signaling cascade, PLC-β hydrolyses phosphatidylinositolbisphosphate to yield inositol trisphosphate and diacylglycerol. As IP3 receptors have sparse or little distribution throughout the pharyngeal nervous system of C.elegans and β-phorbel esters have been shown to have a stimulatory action on synaptic transmission, it has been concluded that it is the DAG component of the cascade that regulates neurotransmitter release. Indeed, in C.elegans DAG regulates UNC-13, a plasma-membrane associated protein critical for vesicle-mediated neurotransmitter release and mutational studies have shown that two UNC-13 reduction of function mutants show resistance to emodepside, observations supporting this hypothesized mechanism of action. The mechanism by which activation of UNC-13 results in neurotransmitter release is through interaction with the synaptosomal membrane proteinsyntaxin, with UNC-13 binding to the N-terminus of syntaxin and promoting the switch from the closed form of syntaxin to its open formation so that SNARE complex formation can be achieved, thereby allowing vesicle fusion and release to take place. At a molecular level, the net result of the activation of this pathway, is the spontaneous stimulation of inhibitory PF1-like neuropeptide release which then acts on the post-synaptic membrane of the nematode, having an inhibitory effect thereby either inducing paralysis or inhibiting pharyngeal pumping, both of which ultimately result in the death of the organism. Mutational studies involving LAT-1 knockout and LAT-2 gene deletion mutants have revealed that the role of latrophilin receptors in the different tissues that they are expressed differs between subtypes, with LAT-1 being expressed in the pharynx of C.elegans and LAT-2 having a role in locomotion. In addition to exerting an effect on the nematode via binding to Latrophilin receptors, there is also recent evidence that indicates that emodepside also interacts with the BK potassium channel coded by the gene Slo-1. This protein is a member of the 6 transmembrane helix structural class of potassium ion channels with each subunit consisting of 6 transmembrane helices and 1 P domain. These subunits group together to form high conductance BK-type channels that are gated by both membrane potential and intracellular calcium levels, with their physiological role being to regulate the excitability of neurons and muscle fibres, through the way in which they participate in action potential repolariziation. The presumable effect that emodepside interaction with these channels would exert on the neuron would be to activate the channel causing potassium ion efflux, hyper-polarization and subsequent inhibition of excitatory neurotransmitter effect, having an inhibitory effect on synaptic transmission, the production of postsynaptic action potentials and ultimately muscle contraction. Which out of Latrophilin receptors and BK-potassium channels is emodepside's primary site of action remains to be completely deduced. Both LAT-1/LAT-2 and slo-1 mutants show significant resistance to emodepside with it being conceivable that the presence of both is required for emodepside to induce its full effect.
Therapeutic use
The patent for emodepside is owned by the Bayer Health Care group and is sold in combination with another anthelmintic for topical application under the tradename Profender.
