Emodepside

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Emodepside
Emodepside.png
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PubChem CID
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Chemical and physical data
Formula C60H90N6O14
Molar mass 1119.408 g·mol−1
3D model (JSmol)
  • CC(C)C[C@H]1C(=O)O[C@H](Cc2ccc(N3CCOCC3)cc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](Cc2ccc(N3CCOCC3)cc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N1C
  • InChI=1S/C60H90N6O14/c1-37(2)31-47-57(71)77-41(9)53(67)61(11)50(34-40(7)8)60(74)80-52(36-44-17-21-46(22-18-44)66-25-29-76-30-26-66)56(70)64(14)48(32-38(3)4)58(72)78-42(10)54(68)62(12)49(33-39(5)6)59(73)79-51(55(69)63(47)13)35-43-15-19-45(20-16-43)65-23-27-75-28-24-65/h15-22,37-42,47-52H,23-36H2,1-14H3/t41-,42-,47+,48+,49+,50+,51-,52-/m1/s1 Yes check.svgY
  • Key:ZMQMTKVVAMWKNY-YSXLEBCMSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Emodepside is an anthelmintic drug that is effective against a number of gastrointestinal nematodes, is licensed for use in cats [1] and belongs to the class of drugs known as the octadepsipeptides, [2] a relatively new class of anthelmintic (research into these compounds began in the early 1990s), [3] which are suspected to achieve their anti-parasitic effect by a novel mechanism of action due to their ability to kill nematodes resistant to other anthelmintics. [4]

Contents

Synthesis

Figure 1: Camellia japonica Camellia japonica 'Pink Perfection'.jpg
Figure 1: Camellia japonica

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 G-protein coupled receptors called latrophilins, [6] first identified as being target proteins for α-latrotoxin (the other target protein of α-LTX being neurexin, [7] a membrane receptor with laminin-like extracellular domains [8] ), a component of black widow spider venom that can cause paralysis and subsequent death in nematodes and humans alike. LAT-1 (1014 amino acids, 113 KDa coded by the B0457.1 gene) and LAT-2 (1338 amino acids, 147 KDa coded by the B0286.2 gene) [9] are located presynaptically at the neuromuscular junction in Caenorhabditis elegans [2] and share 21% amino acid identity with each other [6] (the amino acid sequence homology LAT-1 shares with rat, bovine and human latrophilins has been shown to be 22, 23 and 21% respectively [6] ).

Figure 2: Hypothesized structure of the LAT-1 receptor. Ref: An original drawing by James Buckley based on information from. Lat1.JPG
Figure 2: Hypothesized structure of the LAT-1 receptor. Ref: An original drawing by James Buckley based on information from.

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 inositol trisphosphate (IP3) and diacylglycerol (DAG). [10] As IP3 receptors have sparse or little distribution throughout the pharyngeal nervous system of C.elegans [11] (one of the tissues where LAT-1 agonists such as α-LTX and emodepside have their most predominant effects) [6] and β-phorbel esters (which mimic the effects of DAG) have been shown to have a stimulatory action on synaptic transmission, [12] it has been concluded that it is the DAG component of the cascade that regulates neurotransmitter release. [6]

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 neurotransmitter release (the ultimate result of latrophilin activation) is through interaction with the synaptosomal membrane protein syntaxin, [6] [14] with UNC-13 binding to the N-terminus of syntaxin and promoting the switch from the closed form of syntaxin (which is incompatible with SNARE complex synaptobrevin, SNAP-25 and syntaxin formation) to its open formation so that SNARE complex formation can be achieved, thereby allowing vesicle fusion and release to take place. [14]

At a molecular level, the net result of the activation of this pathway, is the spontaneous stimulation of inhibitory PF1-like neuropeptide release (this is suspected due to Emodepside's inhibition of acetylcholine-elicited muscle contraction requiring both calcium ions and extracellular potassium ions, similar to the action of PF1/PF2). Although in experiments on synaptosomes, α-LTX triggered non-calcium dependent exocytosis of vesicles containing acetylcholine, glutamate and GABA, [15] both glutamate [6] and GABA [15] have been ruled out as the sole neurotransmitters responsible for emodepside's action) which then acts on the post-synaptic membrane (i.e. the pharyngeal/muscle 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.[ citation needed ]

Diagram Mofaemo1.JPG
Diagram

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]

Related Research Articles

<span class="mw-page-title-main">Chemical synapse</span> Biological junctions through which neurons signals can be sent

Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. IPSPs were first investigated in motorneurons by David P. C. Lloyd, John Eccles and Rodolfo Llinás in the 1950s and 1960s. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell to cell signalling. Inhibitory presynaptic neurons release neurotransmitters that then bind to the postsynaptic receptors; this induces a change in the permeability of the postsynaptic neuronal membrane to particular ions. An electric current that changes the postsynaptic membrane potential to create a more negative postsynaptic potential is generated, i.e. the postsynaptic membrane potential becomes more negative than the resting membrane potential, and this is called hyperpolarisation. To generate an action potential, the postsynaptic membrane must depolarize—the membrane potential must reach a voltage threshold more positive than the resting membrane potential. Therefore, hyperpolarisation of the postsynaptic membrane makes it less likely for depolarisation to sufficiently occur to generate an action potential in the postsynaptic neurone.

<span class="mw-page-title-main">Graded potential</span> Changes in membrane potential varying in size

Graded potentials are changes in membrane potential that vary in size, as opposed to being all-or-none. They include diverse potentials such as receptor potentials, electrotonic potentials, subthreshold membrane potential oscillations, slow-wave potential, pacemaker potentials, and synaptic potentials, which scale with the magnitude of the stimulus. They arise from the summation of the individual actions of ligand-gated ion channel proteins, and decrease over time and space. They do not typically involve voltage-gated sodium and potassium channels. These impulses are incremental and may be excitatory or inhibitory. They occur at the postsynaptic dendrite in response to presynaptic neuron firing and release of neurotransmitter, or may occur in skeletal, smooth, or cardiac muscle in response to nerve input. The magnitude of a graded potential is determined by the strength of the stimulus.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

<span class="mw-page-title-main">Synaptic vesicle</span> Neurotransmitters that are released at the synapse

In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5 nanometers (nm) with a standard deviation of 5.1 nm.

<span class="mw-page-title-main">End-plate potential</span>

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">SNARE protein</span> Protein family

SNARE proteins – "SNAPREceptors" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells, and some numbers in plants. The primary role of SNARE proteins is to mediate the fusion of vesicles with the target membrane; this notably mediates exocytosis, but can also mediate the fusion of vesicles with membrane-bound compartments. The best studied SNAREs are those that mediate the release of synaptic vesicles containing neurotransmitters in neurons. These neuronal SNAREs are the targets of the neurotoxins responsible for botulism and tetanus produced by certain bacteria.

A latrotoxin is a high-molecular mass neurotoxin found in the venom of spiders of the genus Latrodectus as well as at least one species of another genus in the same family, Steatoda nobilis. Latrotoxins are the main active components of the venom and are responsible for the symptoms of latrodectism.

<span class="mw-page-title-main">STX1A</span> Protein-coding gene in the species Homo sapiens

Syntaxin-1A is a protein that in humans is encoded by the STX1A gene.

Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.

<span class="mw-page-title-main">Dendritic spike</span> Action potential generated in the dendrite of a neuron

In neurophysiology, a dendritic spike refers to an action potential generated in the dendrite of a neuron. Dendrites are branched extensions of a neuron. They receive electrical signals emitted from projecting neurons and transfer these signals to the cell body, or soma. Dendritic signaling has traditionally been viewed as a passive mode of electrical signaling. Unlike its axon counterpart which can generate signals through action potentials, dendrites were believed to only have the ability to propagate electrical signals by physical means: changes in conductance, length, cross sectional area, etc. However, the existence of dendritic spikes was proposed and demonstrated by W. Alden Spencer, Eric Kandel, Rodolfo Llinás and coworkers in the 1960s and a large body of evidence now makes it clear that dendrites are active neuronal structures. Dendrites contain voltage-gated ion channels giving them the ability to generate action potentials. Dendritic spikes have been recorded in numerous types of neurons in the brain and are thought to have great implications in neuronal communication, memory, and learning. They are one of the major factors in long-term potentiation.

<span class="mw-page-title-main">Axon terminal</span> Nerve fiber part

Axon terminals are distal terminations of the branches of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell that conducts electrical impulses called action potentials away from the neuron's cell body in order to transmit those impulses to other neurons, muscle cells or glands. In the central nervous system, most presynaptic terminals are actually formed along the axons, not at their ends.

Cellular neuroscience is a branch of neuroscience concerned with the study of neurons at a cellular level. This includes morphology and physiological properties of single neurons. Several techniques such as intracellular recording, patch-clamp, and voltage-clamp technique, pharmacology, confocal imaging, molecular biology, two photon laser scanning microscopy and Ca2+ imaging have been used to study activity at the cellular level. Cellular neuroscience examines the various types of neurons, the functions of different neurons, the influence of neurons upon each other, and how neurons work together.

Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles can also fuse with other target cell compartments, such as a lysosome. Exocytosis occurs when secretory vesicles transiently dock and fuse at the base of cup-shaped structures at the cell plasma membrane called porosome, the universal secretory machinery in cells. Vesicle fusion may depend on SNARE proteins in the presence of increased intracellular calcium (Ca2+) concentration.

<span class="mw-page-title-main">Gating (electrophysiology)</span>

In electrophysiology, the term gating refers to the opening (activation) or closing of ion channels. This change in conformation is a response to changes in transmembrane voltage.

Munc-18 proteins are the mammalian homologue of UNC-18 and are a member of the Sec1/Munc18-like (SM) protein family. Munc-18 proteins have been identified as essential components of the synaptic vesicle fusion protein complex and are crucial for the regulated exocytosis of neurons and neuroendocrine cells.

<span class="mw-page-title-main">Active zone</span>

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

Neurotransmitters are released into a synapse in packaged vesicles called quanta. One quantum generates a miniature end plate potential (MEPP) which is the smallest amount of stimulation that one neuron can send to another neuron. Quantal release is the mechanism by which most traditional endogenous neurotransmitters are transmitted throughout the body. The aggregate sum of many MEPPs is an end plate potential (EPP). A normal end plate potential usually causes the postsynaptic neuron to reach its threshold of excitation and elicit an action potential. Electrical synapses do not use quantal neurotransmitter release and instead use gap junctions between neurons to send current flows between neurons. The goal of any synapse is to produce either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP), which generate or repress the expression, respectively, of an action potential in the postsynaptic neuron. It is estimated that an action potential will trigger the release of approximately 20% of an axon terminal's neurotransmitter load.

References

  1. ↑ "Profender? Spot-on at a glance". Archived from the original on 2007-01-11. Retrieved 2007-01-10.
  2. 1 2 Willson J, Amliwala K, Harder A, Holden-Dye L, Walker RJ (January 2003). "The effect of the anthelmintic emodepside at the neuromuscular junction of the parasitic nematode Ascaris suum". Parasitology. 126 (Pt 1): 79–86. doi:10.1017/S0031182002002639. PMID   12613766. S2CID   21831523.
  3. 1 2 Harder A, Holden-Dye L, Walker R, Wunderlich F (October 2005). "Mechanisms of action of emodepside". Parasitology Research. 97 (Suppl 1): S1–S10. doi:10.1007/s00436-005-1438-z. PMID   16228263. S2CID   86636553.
  4. ↑ Harder A, Schmitt-Wrede HP, Krücken J, Marinovski P, Wunderlich F, Willson J, et al. (September 2003). "Cyclooctadepsipeptides--an anthelmintically active class of compounds exhibiting a novel mode of action". International Journal of Antimicrobial Agents. 22 (3): 318–331. doi:10.1016/S0924-8579(03)00219-X. PMID   13678839.
  5. ↑ Geßner G, Meder S, Rink T, Boheim G, Harder A, Jeschke P, Scherkenbeck J, Londershausen M (December 1996). "Ionophore and anthelmintic activity of PF 1022A, a cyclooctadepsipeptide, are not related". Pesticide Science. 48 (4): 399–407. doi:10.1002/(SICI)1096-9063(199612)48:4<399::AID-PS503>3.0.CO;2-K.
  6. 1 2 3 4 5 6 7 8 9 10 Willson J, Amliwala K, Davis A, Cook A, Cuttle MF, Kriek N, et al. (August 2004). "Latrotoxin receptor signaling engages the UNC-13-dependent vesicle-priming pathway in C. elegans". Current Biology. 14 (15): 1374–1379. doi: 10.1016/j.cub.2004.07.056 . PMID   15296755.
  7. ↑ Davletov BA, Meunier FA, Ashton AC, Matsushita H, Hirst WD, Lelianova VG, et al. (July 1998). "Vesicle exocytosis stimulated by alpha-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+". The EMBO Journal. 17 (14): 3909–3920. doi:10.1093/emboj/17.14.3909. PMC   1170726 . PMID   9670008.
  8. ↑ Saibil HR (January 2000). "The black widow's versatile venom". Nature Structural Biology. 7 (1): 3–4. doi:10.1038/71190. PMID   10625413. S2CID   28185969.
  9. 1 2 "Wormbase". Archived from the original on 2017-04-20. Retrieved 2022-01-15.
  10. ↑ The molecular biology of the cell - Alberts et al.
  11. ↑ Baylis HA, Furuichi T, Yoshikawa F, Mikoshiba K, Sattelle DB (November 1999). "Inositol 1,4,5-trisphosphate receptors are strongly expressed in the nervous system, pharynx, intestine, gonad and excretory cell of Caenorhabditis elegans and are encoded by a single gene (itr-1)". Journal of Molecular Biology. 294 (2): 467–476. doi:10.1006/jmbi.1999.3229. PMID   10610772.
  12. ↑ Majewski H, Iannazzo L (August 1998). "Protein kinase C: a physiological mediator of enhanced transmitter output". Progress in Neurobiology. 55 (5): 463–475. doi:10.1016/S0301-0082(98)00017-3. PMID   9670214. S2CID   9063590.
  13. ↑ Aravamudan B, Fergestad T, Davis WS, Rodesch CK, Broadie K (November 1999). "Drosophila UNC-13 is essential for synaptic transmission". Nature Neuroscience. 2 (11): 965–971. doi:10.1038/14764. PMID   10526334. S2CID   24641836.
  14. 1 2 Söllner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE (November 1993). "A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion". Cell. 75 (3): 409–418. doi:10.1016/0092-8674(93)90376-2. PMID   8221884. S2CID   26906457.
  15. 1 2 Khvotchev M, Lonart G, Südhof TC (2000). "Role of calcium in neurotransmitter release evoked by alpha-latrotoxin or hypertonic sucrose". Neuroscience. 101 (3): 793–802. doi:10.1016/s0306-4522(00)00378-x. PMID   11113328. S2CID   54256700.
  16. ↑ 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.
  17. 1 2 Salkoff L, Wei AD, Baban B, Butler A, Fawcett G, Ferreira G, Santi CM (December 2005). "Potassium channels in C. elegans". WormBook : The Online Review of C. Elegans Biology: 1–15. doi:10.1895/wormbook.1.42.1. PMC   4781360 . PMID   18050399.
  18. ↑ Schreiber M, Salkoff L (September 1997). "A novel calcium-sensing domain in the BK channel". Biophysical Journal. 73 (3): 1355–1363. Bibcode:1997BpJ....73.1355S. doi:10.1016/S0006-3495(97)78168-2. PMC   1181035 . PMID   9284303.
  19. ↑ Araque A, Buño W (October 1999). "Fast BK-type channel mediates the Ca(2+)-activated K(+) current in crayfish muscle". Journal of Neurophysiology. 82 (4): 1655–1661. doi:10.1152/jn.1999.82.4.1655. PMID   10515956.
  20. ↑ Altreuther G, Buch J, Charles SD, Davis WL, Krieger KJ, Radeloff I (October 2005). "Field evaluation of the efficacy and safety of emodepside/praziquantel spot-on solution against naturally acquired nematode and cestode infections in domestic cats". Parasitology Research. 97 (Suppl 1): S58–S64. doi:10.1007/s00436-005-1445-0. PMID   16228276. S2CID   3324872.
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