Misplaced Pages

Emodepside: Difference between revisions

Article snapshot taken from Wikipedia with creative commons attribution-sharealike license. Give it a read and then ask your questions in the chat. We can research this topic together.
Browse history interactively
Page 1
Page 2
← Previous editContent deleted Content addedVisualWikitext
Revision as of 21:04, 31 August 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{drugbox}} (no changed fields - added verified revid - updated 'ChEMBL_Ref', 'ChEBI_Ref', 'KEGG_Ref', 'ChEBI_Ref') per Chem/Drugbox validation (report errors or [[user talk:CheMoB← Previous edit Latest revision as of 05:25, 26 December 2024 edit undoWhywhenwhohow (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers49,206 edits added Category:Veterinary drugs using HotCat 
(49 intermediate revisions by 33 users not shown)
Line 1: Line 1:
{{Short description|Chemical compound}}
{{Drugbox
{{Infobox drug
⚫ | verifiedrevid = 444354135
| Verifiedfields = changed
⚫ | IUPAC_name =
| Watchedfields = changed
⚫ | verifiedrevid = 447724337
⚫ | IUPAC_name =
| image = emodepside.png | image = emodepside.png


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename =
| Drugs.com = {{drugs.com|international|emodepside}} | Drugs.com = {{drugs.com|international|emodepside}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = | pregnancy_category =
⚫ | routes_of_administration =
| ATCvet = yes
⚫ | ATC_prefix = P52
⚫ | ATC_suffix = AX60
| ATC_supplemental = (combination with ])

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA = Rx-only
| legal_CA_comment =
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = | legal_status =
⚫ | routes_of_administration =


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = | bioavailability =
| protein_bound = | protein_bound =
| metabolism = | metabolism =
| elimination_half-life = | elimination_half-life =
| excretion = | excretion =


<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 155030-63-0 | CAS_number = 155030-63-0
⚫ | ATC_prefix = none
⚫ | ATC_suffix =
| PubChem = 6918632 | PubChem = 6918632
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = | DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5293825 | ChemSpiderID = 5293825
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 78739
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 2104404
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = YZ647Y5GC9 | UNII = YZ647Y5GC9


<!--Chemical data--> <!--Chemical data-->
| C=60 | H=90 | N=6 | O=14 | C=60 | H=90 | N=6 | O=14
⚫ | smiles = CC(C)C1C(=O)O(Cc2ccc(N3CCOCC3)cc2)C(=O)N(C)(CC(C)C)C(=O)O(C)C(=O)N(C)(CC(C)C)C(=O)O(Cc2ccc(N3CCOCC3)cc2)C(=O)N(C)(CC(C)C)C(=O)O(C)C(=O)N1C
| molecular_weight = 1119.39
⚫ | smiles = O=C1N(C)(C(=O)O(C(=O)N(C)(C(=O)O(C(=O)N(C)(C(=O)O(C(=O)N(C)(C(=O)O1Cc3ccc(N2CCOCC2)cc3)CC(C)C)C)CC(C)C)Cc5ccc(N4CCOCC4)cc5)CC(C)C)C)CC(C)C
| InChI = 1/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
| InChIKey = ZMQMTKVVAMWKNY-YSXLEBCMBY
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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 | StdInChI = 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
Line 47: Line 56:
| StdInChIKey = ZMQMTKVVAMWKNY-YSXLEBCMSA-N | StdInChIKey = ZMQMTKVVAMWKNY-YSXLEBCMSA-N
}} }}
'''Emodepside''' is an ] drug that is effective against a number of ] ]s, is licensed for use in ]s<ref>http://www.profender.no/128/Product/At_a_Glance.htm</ref> and belongs to the class of drugs known as the ''octadepsipeptides'',<ref name="Willson 2003">{{cite journal |author=Willson J, Amliwala K, Harder A, Holden-Dye L, Walker RJ |title=The effect of the anthelmintic emodepside at the neuromuscular junction of the parasitic nematode Ascaris suum |journal=Parasitology |volume=126 |issue=Pt 1 |pages=79–86 |year=2003 |pmid=12613766 |doi=10.1017/S0031182002002639}}</ref> a relatively new class of ] (research into these compounds began in the early 1990s),<ref name="Horder" /> which are suspected to achieve their anti-parasitic effect by a novel ] due to their ability to kill ] resistant to other anthelmintics.<ref>{{cite journal |author=Harder A, Schmitt-Wrede HP, Krücken J, ''et al.'' |title=Cyclooctadepsipeptides--an anthelmintically active class of compounds exhibiting a novel mode of action |journal=Int. J. Antimicrob. Agents |volume=22 |issue=3 |pages=318–31 |year=2003 |pmid=13678839 |doi=10.1016/S0924-8579(03)00219-X}}</ref> '''Emodepside''' is an ] drug that is effective against a number of ] ]s, is licensed for use in ]s<ref>{{Cite web |url=http://www.profender.no/128/Product/At_a_Glance.htm |title=Profender? Spot-on at a glance |access-date=2007-01-10 |archive-url=https://web.archive.org/web/20070111193009/http://www.profender.no/128/Product/At_a_Glance.htm |archive-date=2007-01-11 |url-status=dead }}</ref> and belongs to the class of drugs known as the ''octadepsipeptides'',<ref name="Willson 2003">{{cite journal | vauthors = Willson J, Amliwala K, Harder A, Holden-Dye L, Walker RJ | title = The effect of the anthelmintic emodepside at the neuromuscular junction of the parasitic nematode Ascaris suum | journal = Parasitology | volume = 126 | issue = Pt 1 | pages = 79–86 | date = January 2003 | pmid = 12613766 | doi = 10.1017/S0031182002002639 | s2cid = 21831523 }}</ref> a relatively new class of ] (research into these compounds began in the early 1990s),<ref name="Harder_2005" /> which are suspected to achieve their anti-parasitic effect by a novel ] due to their ability to kill ] resistant to other anthelmintics.<ref>{{cite journal | vauthors = Harder A, Schmitt-Wrede HP, Krücken J, Marinovski P, Wunderlich F, Willson J, Amliwala K, Holden-Dye L, Walker R | display-authors = 6 | title = Cyclooctadepsipeptides--an anthelmintically active class of compounds exhibiting a novel mode of action | journal = International Journal of Antimicrobial Agents | volume = 22 | issue = 3 | pages = 318–331 | date = September 2003 | pmid = 13678839 | doi = 10.1016/S0924-8579(03)00219-X }}</ref>


==Synthesis== ==Synthesis==
] ]
Emodepside is synthesised by attaching a morpholine ring “at the paraposition of each of the two D-phenyllactic acids” to ''PF1022A'', a ] of ''Mycelia sterile'', a ] that inhabits the leaves of ''] japonica''<ref name="Horder">Mechanisms of action of emodespide - A Horder et al.</ref> – a flowering ]. Emodepside is synthesised by attaching a morpholine ring “at the paraposition of each of the two D-phenyllactic acids” to ''PF1022A'', a ] of ''Mycelia sterile'', a ] that inhabits the leaves of ''] japonica''<ref name="Harder_2005">{{cite journal | vauthors = Harder A, Holden-Dye L, Walker R, Wunderlich F | title = Mechanisms of action of emodepside | journal = Parasitology Research | volume = 97 | issue = Suppl 1| pages = S1–S10 | date = October 2005 | pmid = 16228263 | doi = 10.1007/s00436-005-1438-z | s2cid = 86636553 | url = }}</ref> – a flowering ].
<br clear="left"> {{clear|left}}


==Anthelmintic effects== ==Anthelmintic effects==
When applied to ], emodepside has been shown to have a range of effects, inhibiting muscle in the parasitic nematode ''Ascaris sum''<ref>Ionophore and anthelmintic activity of PF 1022A, a cyclooctadepsipeptide, are not related - Gesner et al.</ref> and inhibiting locomotive and pharyngeal movement in ] in addition to having effects in other tissues such as the inhibition of egg laying.<ref name="Willson 2004">{{cite journal |author=Willson J, Amliwala K, Davis A, ''et al.'' |title=Latrotoxin receptor signaling engages the UNC-13-dependent vesicle-priming pathway in C. elegans |journal=Curr. Biol. |volume=14 |issue=15 |pages=1374–9 |year=2004 |pmid=15296755 |doi=10.1016/j.cub.2004.07.056}}</ref> When applied to nematodes, emodepside has been shown to have a range of effects, inhibiting muscle in the parasitic nematode ''Ascaris sum'',<ref>{{cite journal | vauthors = Geßner G, Meder S, Rink T, Boheim G, Harder A, Jeschke P, Scherkenbeck J, Londershausen M | title = Ionophore and anthelmintic activity of PF 1022A, a cyclooctadepsipeptide, are not related. | journal = Pesticide Science | date = December 1996 | volume = 48 | issue = 4 | pages = 399–407 | doi = 10.1002/(SICI)1096-9063(199612)48:4<399::AID-PS503>3.0.CO;2-K }}</ref> and inhibiting locomotive and pharyngeal movement in '']'' in addition to having effects in other tissues such as the inhibition of egg laying.<ref name="Willson_2004">{{cite journal | vauthors = Willson J, Amliwala K, Davis A, Cook A, Cuttle MF, Kriek N, Hopper NA, O'Connor V, Harder A, Walker RJ, Holden-Dye L | display-authors = 6 | title = Latrotoxin receptor signaling engages the UNC-13-dependent vesicle-priming pathway in C. elegans | journal = Current Biology | volume = 14 | issue = 15 | pages = 1374–1379 | date = August 2004 | pmid = 15296755 | doi = 10.1016/j.cub.2004.07.056 | doi-access = free | bibcode = 2004CBio...14.1374W }}</ref>


==Mechanism of action== ==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 ] called ''latrophilins'',<ref name="Willson 2004" /> first identified as being target proteins for α-latrotoxin (the other target protein of α-LTX being neurexin,<ref>{{cite journal |author=Davletov BA, Meunier FA, Ashton AC, ''et al.'' |title=Vesicle exocytosis stimulated by alpha-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+ |journal=EMBO J. |volume=17 |issue=14 |pages=3909–20 |year=1998 |pmid=9670008 |doi=10.1093/emboj/17.14.3909 |pmc=1170726}}</ref> a membrane receptor with laminin-like extracellular domains<ref>{{cite journal |author=Saibil HR |title=The black widow's versatile venom |journal=Nat. Struct. Biol. |volume=7 |issue=1 |pages=3–4 |year=2000 |pmid=10625413 |doi=10.1038/71190}}</ref>), a component of ] venom that can cause ] 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)<ref name="Wormbase"></ref> are located presynaptically at the ] in ''Caenorhabditis elegans''<ref name="Willson 2003" /> and share 21% amino acid identity with each other<ref name="Willson 2004" /> (the amino acid sequence homology LAT-1 shares with rat, bovine and human latrophilins has been shown to be 22, 23 and 21% respectively<ref name="Willson 2004" />). One of the ways in which this drug achieves its effects has been shown to be through binding to a group of ] called ''latrophilins'',<ref name="Willson_2004" /> first identified as being target proteins for α-latrotoxin (the other target protein of α-LTX being neurexin,<ref>{{cite journal | vauthors = Davletov BA, Meunier FA, Ashton AC, Matsushita H, Hirst WD, Lelianova VG, Wilkin GP, Dolly JO, Ushkaryov YA | display-authors = 6 | title = Vesicle exocytosis stimulated by alpha-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+ | journal = The EMBO Journal | volume = 17 | issue = 14 | pages = 3909–3920 | date = July 1998 | pmid = 9670008 | pmc = 1170726 | doi = 10.1093/emboj/17.14.3909 }}</ref> a membrane receptor with laminin-like extracellular domains<ref>{{cite journal | vauthors = Saibil HR | title = The black widow's versatile venom | journal = Nature Structural Biology | volume = 7 | issue = 1 | pages = 3–4 | date = January 2000 | pmid = 10625413 | doi = 10.1038/71190 | s2cid = 28185969 }}</ref>), a component of ] venom that can cause ] 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)<ref name="Wormbase">{{Cite web |url=http://www.wormbase.org/ |title=Wormbase |access-date=2022-01-15 |archive-date=2017-04-20 |archive-url=https://web.archive.org/web/20170420234209/http://www.wormbase.org/ |url-status=dead }}</ref> are located presynaptically at the ] in ''Caenorhabditis elegans''<ref name="Willson 2003" /> and share 21% amino acid identity with each other<ref name="Willson_2004" /> (the amino acid sequence homology LAT-1 shares with rat, bovine and human latrophilins has been shown to be 22, 23 and 21% respectively<ref name="Willson_2004" />).

] ]


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 ]-C-β, a protein that has been identified as being key to the modulation of regulatory pathways of vesicle release in ''C.elegans''.<ref name="Willson 2004" /> 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 ]-C-β, a protein that has been identified as being key to the modulation of regulatory pathways of vesicle release in ''C.elegans''.<ref name="Willson_2004" />


In its signaling cascade, PLC-β (like other phospholipases) hydrolyses phosphatidylinositolbisphosphate to yield ] (IP3) and ] (DAG).<ref>The molecular biology of the cell - Alberts et al.</ref> As IP3 receptors have sparse or little distribution throughout the pharyngeal nervous system of C.elegans<ref>{{cite journal |author=Baylis HA, Furuichi T, Yoshikawa F, Mikoshiba K, Sattelle DB |title=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=J. Mol. Biol. |volume=294 |issue=2 |pages=467–76 |year=1999 |pmid=10610772 |doi=10.1006/jmbi.1999.3229}}</ref> (one of the tissues where LAT-1 agonists such as α-LTX and emodepside have their most predominant effects)<ref name="Willson 2004" /> and β-phorbel esters (which mimic the effects of DAG) have been shown to have a stimulatory action on ],<ref>{{cite journal |author=Majewski H, Iannazzo L |title=Protein kinase C: a physiological mediator of enhanced transmitter output |journal=Prog. Neurobiol. |volume=55 |issue=5 |pages=463–75 |year=1998 |pmid=9670214 |doi=10.1016/S0301-0082(98)00017-3}}</ref> it has been concluded that it is the DAG component of the cascade that regulates ] release.<ref name="Willson 2004" /> In its signaling cascade, PLC-β (like other phospholipases) hydrolyses phosphatidylinositolbisphosphate to yield ] (IP3) and ] (DAG).<ref>The molecular biology of the cell - Alberts et al.</ref> As IP3 receptors have sparse or little distribution throughout the pharyngeal nervous system of C.elegans<ref>{{cite journal | vauthors = Baylis HA, Furuichi T, Yoshikawa F, Mikoshiba K, Sattelle DB | title = 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 = Journal of Molecular Biology | volume = 294 | issue = 2 | pages = 467–476 | date = November 1999 | pmid = 10610772 | doi = 10.1006/jmbi.1999.3229 }}</ref> (one of the tissues where LAT-1 agonists such as α-LTX and emodepside have their most predominant effects)<ref name="Willson_2004" /> and β-phorbel esters (which mimic the effects of DAG) have been shown to have a stimulatory action on ],<ref>{{cite journal | vauthors = Majewski H, Iannazzo L | title = Protein kinase C: a physiological mediator of enhanced transmitter output | journal = Progress in Neurobiology | volume = 55 | issue = 5 | pages = 463–475 | date = August 1998 | pmid = 9670214 | doi = 10.1016/S0301-0082(98)00017-3 | s2cid = 9063590 }}</ref> it has been concluded that it is the DAG component of the cascade that regulates ] release.<ref name="Willson_2004" />


Indeed, in C.elegans DAG regulates UNC-13, a plasma-membrane associated protein critical for vesicle-mediated neurotransmitter release<ref>{{cite journal |author=Aravamudan B, Fergestad T, Davis WS, Rodesch CK, Broadie K |title=Drosophila UNC-13 is essential for synaptic transmission |journal=Nat. Neurosci. |volume=2 |issue=11 |pages=965–71 |year=1999 |pmid=10526334 |doi=10.1038/14764}}</ref> and mutational studies have shown that two UNC-13 reduction of function mutants show resistance to emodepside, observations supporting this hypothesized mechanism of action. Indeed, in C.elegans DAG regulates UNC-13, a plasma-membrane associated protein critical for vesicle-mediated neurotransmitter release<ref>{{cite journal | vauthors = Aravamudan B, Fergestad T, Davis WS, Rodesch CK, Broadie K | title = Drosophila UNC-13 is essential for synaptic transmission | journal = Nature Neuroscience | volume = 2 | issue = 11 | pages = 965–971 | date = November 1999 | pmid = 10526334 | doi = 10.1038/14764 | s2cid = 24641836 }}</ref> 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 ] release (the ultimate result of latrophilin activation) is through interaction with the synaptosomal membrane protein ],<ref name="Willson 2004" /><ref name="Soellner 1993">{{cite journal |author=Söllner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE |title=A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion |journal=Cell |volume=75 |issue=3 |pages=409–18 |year=1993 |pmid=8221884 |doi=10.1016/0092-8674(93)90376-2}}</ref> with UNC-13 binding to the N-terminus of syntaxin and promoting the switch from the closed form of ] (which is incompatible with SNARE complex synaptobrevin, ] and ] formation) to its open formation so that SNARE complex formation can be achieved, thereby allowing ] fusion and release to take place.<ref name="Soellner 1993" /> The mechanism by which activation of UNC-13 results in ] release (the ultimate result of latrophilin activation) is through interaction with the synaptosomal membrane protein ],<ref name="Willson_2004" /><ref name="Soellner 1993">{{cite journal | vauthors = Söllner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE | title = A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion | journal = Cell | volume = 75 | issue = 3 | pages = 409–418 | date = November 1993 | pmid = 8221884 | doi = 10.1016/0092-8674(93)90376-2 | s2cid = 26906457 }}</ref> with UNC-13 binding to the N-terminus of syntaxin and promoting the switch from the closed form of ] (which is incompatible with SNARE complex synaptobrevin, ] and ] formation) to its open formation so that SNARE complex formation can be achieved, thereby allowing ] fusion and release to take place.<ref name="Soellner 1993" />


At a molecular level, the net result of the activation of this pathway, is the spontaneous stimulation of inhibitory PF1-like ] 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 ], ] and ],<ref name="Khvotchev">Role of calcium in neurotransmitter release evoked by alpha-latrotoxin or hypertonic sucrose - Khvotchev et al.</ref> both ]<ref name="Willson 2004" /> and ]<ref name="Khvotchev" /> 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 ] or inhibiting pharyngeal pumping, both of which ultimately result in the death of the organism. At a molecular level, the net result of the activation of this pathway, is the spontaneous stimulation of inhibitory PF1-like ] 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 ], ] and ],<ref name="Khvotchev">{{cite journal | vauthors = Khvotchev M, Lonart G, Südhof TC | title = Role of calcium in neurotransmitter release evoked by alpha-latrotoxin or hypertonic sucrose | journal = Neuroscience | volume = 101 | issue = 3 | pages = 793–802 | date = 2000 | pmid = 11113328 | doi = 10.1016/s0306-4522(00)00378-x | s2cid = 54256700 }}</ref> both ]<ref name="Willson_2004" /> and ]<ref name="Khvotchev" /> 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 ] or inhibiting pharyngeal pumping, both of which ultimately result in the death of the organism.{{citation needed|date=December 2022}}


] ]


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.<ref name="Willson 2004" /> 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.<ref name="Willson_2004" />


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.<ref>A possible mechanism for the action of the novel anthelmintic emodepside, using Ascaris suum body wall muscle preparations - Willson et al.</ref> 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).<ref name="Salkoff">Potassium channels in C. elegans - Salkoff et al.</ref> These subunits group together to form high conductance BK-type channels that are gated by both membrane potential and intracellular calcium levels<ref name="Salkoff" /> (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”),<ref>{{cite journal |author=Schreiber M, Salkoff L |title=A novel calcium-sensing domain in the BK channel |journal=Biophys. J. |volume=73 |issue=3 |pages=1355–63 |year=1997 |pmid=9284303 |doi=10.1016/S0006-3495(97)78168-2 |pmc=1181035 |bibcode=1997BpJ....73.1355S}}</ref> 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).<ref>{{cite journal |author=Araque A, Buño W |title=Fast BK-type channel mediates the Ca(2+)-activated K(+) current in crayfish muscle |journal=J. Neurophysiol. |volume=82 |issue=4 |pages=1655–61 |year=1999 |pmid=10515956 |doi=}}</ref> 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.<ref>{{cite journal | vauthors = Willson J, Holden-Dye L, Harder A, Walker RJ | title = A possible mechanism for the action of the novel anthelmintic emodepside, using Ascaris suum body wall muscle preparations. | journal = Journal of Physiology | date = November 2001 | volume = 536 | issue = S103 | pages = 132P–133P }}</ref> 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).<ref name="Salkoff">{{cite journal | vauthors = Salkoff L, Wei AD, Baban B, Butler A, Fawcett G, Ferreira G, Santi CM | title = Potassium channels in C. elegans | journal = WormBook: The Online Review of C. Elegans Biology | volume = | issue = | pages = 1–15 | date = December 2005 | pmid = 18050399 | pmc = 4781360 | doi = 10.1895/wormbook.1.42.1 | url = }}</ref> These subunits group together to form high conductance BK-type channels that are gated by both membrane potential and intracellular calcium levels<ref name="Salkoff" /> (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”),<ref>{{cite journal | vauthors = Schreiber M, Salkoff L | title = A novel calcium-sensing domain in the BK channel | journal = Biophysical Journal | volume = 73 | issue = 3 | pages = 1355–1363 | date = September 1997 | pmid = 9284303 | pmc = 1181035 | doi = 10.1016/S0006-3495(97)78168-2 | bibcode = 1997BpJ....73.1355S }}</ref> 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).<ref>{{cite journal | vauthors = Araque A, Buño W | title = Fast BK-type channel mediates the Ca(2+)-activated K(+) current in crayfish muscle | journal = Journal of Neurophysiology | volume = 82 | issue = 4 | pages = 1655–1661 | date = October 1999 | pmid = 10515956 | doi = 10.1152/jn.1999.82.4.1655 }}</ref>


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). 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|date=December 2022}}


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. 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|date=December 2022}}


==Therapeutic use== ==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'''.<ref name="pmid16228276">{{cite journal | vauthors = Altreuther G, Buch J, Charles SD, Davis WL, Krieger KJ, Radeloff I | title = Field evaluation of the efficacy and safety of emodepside/praziquantel spot-on solution against naturally acquired nematode and cestode infections in domestic cats | journal = Parasitology Research | volume = 97 | issue = Suppl 1| pages = S58–S64 | date = October 2005 | pmid = 16228276 | doi = 10.1007/s00436-005-1445-0 | s2cid = 3324872 }}</ref><ref>{{cite web | title=Profender EPAR | website=European Medicines Agency (EMA) | date=27 July 2005 | url=https://www.ema.europa.eu/en/medicines/veterinary/EPAR/profender | access-date=26 December 2024}}</ref><ref>{{cite web | title=Profender PI | website=Union Register of medicinal products | date=29 July 2005 | url=https://ec.europa.eu/health/documents/community-register/html/v054.htm | access-date=26 December 2024}}</ref>
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'''.


==References== == References ==
{{reflist}} {{Reflist}}


]
] ]
] ]
] ]
]

]
]
]