Emodepside
QP52AX60 (WHO) (combination with toltrazuril) | |
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Emodepside is an
Synthesis
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[3] – a flowering shrub.
Anthelmintic effects
When applied to nematodes, emodepside has been shown to have a range of effects, inhibiting muscle in the parasitic nematode Ascaris sum,[5] and inhibiting locomotive and pharyngeal movement in Caenorhabditis elegans in addition to having effects in other tissues such as the inhibition of egg laying.[6]
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
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.[6]
In its signaling cascade, PLC-β (like other phospholipases) hydrolyses phosphatidylinositolbisphosphate to yield
Indeed, in C.elegans DAG regulates UNC-13, a plasma-membrane associated protein critical for vesicle-mediated neurotransmitter release[13] 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
At a molecular level, the net result of the activation of this pathway, is the spontaneous stimulation of inhibitory PF1-like
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 (thereby modulating pharyngeal pumping) and LAT-2 having a role in locomotion.[6]
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.[16] This protein (see figure for structure) 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 (this P domain is conserved in all potassium ion channels and forms the selectivity filter that enables the channel to transport potassium ions across the membrane in great preference to other ions).[17] These subunits group together to form high conductance BK-type channels that are gated by both membrane potential and intracellular calcium levels[17] (this calcium ion sensing ability is accommodated by an intracellular tail region on Slo-like subunits that form a calcium ion binding motif consisting of a run of conserved aspartate residues, termed a “calcium bowl”),[18] 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 (with potassium ion efflux being used to repolarize the cell following depolarization).[19]
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 (acetylcholine if acting at the neuromuscular junction), having an inhibitory effect on synaptic transmission, the production of postsynaptic action potentials and ultimately muscle contraction (manifesting itself as paralysis or reduced pharyngeal pumping).[citation needed]
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 (reduction/loss of function) show significant resistance to emodepside with it being conceivable that the presence of both is required for emodepside to induce its full effect.[citation needed]
Therapeutic use
The patent for emodepside is owned by the Bayer Health Care group and is sold in combination with another anthelmintic (praziquantel) for topical application under the tradename Profender.[20]
References
- ^ "Profender? Spot-on at a glance". Archived from the original on 2007-01-11. Retrieved 2007-01-10.
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- ^ PMID 15296755.
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- ^ a b "Wormbase". Archived from the original on 2017-04-20. Retrieved 2022-01-15.
- ^ The molecular biology of the cell - Alberts et al.
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- ^ S2CID 26906457.
- ^ S2CID 54256700.
- ^ Willson J, Holden-Dye L, Harder A, Walker RJ (November 2001). "A possible mechanism for the action of the novel anthelmintic emodepside, using Ascaris suum body wall muscle preparations". Journal of Physiology. 536 (S103): 132P–133P.
- ^ PMID 18050399.
- PMID 9284303.
- PMID 10515956.
- S2CID 3324872.