Sedmelanotide (Lebitso la lebitso Imcivree®) ke cyclic octapeptide derivative le moloko o latelang o matla le ho khetha melanocortin-4 receptor agonist. Mokelikeli oa melanocortin-4 ke karolo ea bohlokoa ea tsamaiso ea methapo e bohareng matla a homeostasis taolo marangrang.
Setmelanotide e tšoana ka liketso ho endogenous motho melanocortin (joalo ka α-melanocyte stimulating hormone, α-MSH), empa e ntlafalitsoe hore e be matla le ho feta, khethang le ho tsitsisa metabolism hofeta tlhaho ligand.
E bontša tlase haholo EC50 (halofo ea boholo bo sebetsang hantle) bakeng sa batho le rat MC4R–0.27 nM le 0.28 nM ka ho latellana, ka hona e bonts'a matla a eona a phahameng a ho amohela li-receptor.
Setmelanotide e kenya tšebetsong intracellular kampo ho bontša ka ho susumetsa melanocortin-4 receptors tse teng likarolong tse fapaneng tsa boko, ho kenyeletsa le hypothalamus, mme ka hona e laola takatso ya dijo, tšebeliso ea matla le ts'ebetso ea methapo e ikemetseng e kenyelletsang ho feto-fetoha ha taolo ea khatello ea mali ka ho susumetsa li-neuron tsa preganglionic tsamaiso ea methapo ea kutlo.
Ka lebaka la thepa ea eona e phahameng ea ho tlama li-receptor, e sebetsa e le sesebelisoa sa bohlokoa sa lithuto tsa MC4R-liprotheine tsa lisebelisoa (mohlala, MRAP2) tshebeletsano.
Libakeng tsa kliniki, Setmelanotide e fetoletsoe ka katleho ho sethethefatsi sa kalafo se shebaneng le ho alafa liphatsa tsa lefutso tsa botenya bo bakoang ke bofokoli tseleng ea leptin-melanocortin..
E boetse e khutlisa boima ba 'mele bo bakoang ke lithethefatsi (mohlala, risperidone), e na le litlamorao tse khahlanong le ho ruruha li-astrocyte, 'me e ka sebetsa ka mokhoa o ts'oanang le mehato ea metabolic joalo ka thibelo ea caloric—tseo kaofela li bonts’ang boleng ba eona bo phahameng ba saense le ho sebetsa ho ka bang teng mafapheng a mang a lipatlisiso (joalo ka botenya, metabolic syndrome le mathata a neuroendocrine).
Tatelano
Ac-Arg-Cys-{d-Ala}-His-Phe-Arg-Trp-Cys-NH2 (Borokho ba disulfide:Cys2-Cys8)
Nomoro ea CAS
920014-72-8
Foromo ea limolek'hule
C₄₉H₆₈N₁₈O₉S₂
Boima ba Molek'hule
694.91
Patlisiso ea Setmelanotide
1.MC4R Pathway le MOA ea Setmelanotide
MC4R ke G receptor e kopantsoeng le protheine (GPCR) seo se hlalosoang haholo-holo tsamaisong ea methapo e bohareng, haholo-holo ka har'a li-nuclei tse 'maloa tsa hypothalamus.
Libaka tsena li emela libaka tsa mantlha tsa ho lemoha matšoao a metabolic le ho laola boitšoaro ba phepo le ho leka-lekana ha matla.
Maemong a fisioloji, tsela ena ea MC4R e nka karolo ho thibelang takatso ea lijo le ho susumetsa tšebeliso ea matla..
Tsela ena hangata e hlohlelletsoa ke α-melanocyte-stimulating hormone (α-MSH, a POMC e nkiloeng) e hlahisoang ke li-neurons tsa POMC ka har'a khubu ea arcuate.
Ts'ebetso ea MC4R ka α-MSH e baka phokotso ea matšoao a tlase a hatellang takatso ea lijo le ho ja lijo..
Empa haeba ho na le liphetoho ho POMC gene e thibelang motsoako oa α-MSH, MC4R e tla lula "e sa sebetse" hobane ha e fumane ts'ebetso efe kapa efe ke li-ligands tsa eona.
Khatiso ena ea matšoao e fella ka pathological, takatso ea lijo e sa laoleheng le botenya bo bakoang ke lefu.
Ho sibolla lithethefatsi bakeng sa tsela ea MC4R ho ne ho tsebahala haholo ka thata pele ho Setmelanotide.
Li-agonists tsa pele tse neng li sa khethoe tsa MC4R li ile tsa baka litlamorao tse ke keng tsa mamelloa joalo ka ho ba le 'mala oa letlalo le ho se sebetse hantle hoa thobalano ka ho susumetsa tse ling. melanocortin receptors (i.e., MC1R, MC3R, le MC5R).
Morero oa nts'etsopele ea Setmelanotide o ne o otlolohile: ho fihlella khetho e phahameng bakeng sa MC4R ho ntlafatsa litlamorao tsa eona khatellong ea takatso ea lijo le ho eketsa litšenyehelo tsa matla le ho fokotsa litlamorao tse amanang le ho tlama ha sepheo..
Mokhoa oa mantlha oa tlhaho oa agonist ea kantle ea MC4R Setmelanotide ke ho sebetsa joalo ka sebaka sa α-MSH., ho susumetsa MC4R ka kotloloho molemong oa ho lokisa pathophysiology holimo le ho khutlisetsa lets'oao lena la bohlokoa bakeng sa botsitso ba matla..
Litlamorao tsa limolek'hule le lisele tsa Setmelanotide qetellong li fetolela likarabelo tse tebileng tsa 'mele..
Ka ho susumetsa li-neurone tsa MC4R libakeng tsa bohlokoa ho pholletsa le boko joalo ka hypothalamus PVN, Setmelanotide e khona ho:
Boithuto ba Botenya le bo Rare Genetic Obesity Syndromes: Setmelanotide ke sesebelisoa sa bohlokoa ho ithuteng tšebetso ea tsela ea MC4R.
Haholo-holo, e bontšitsoe hore e sebetsa hantle ho phekola mefuta e sa tloaelehang ea liphatsa tsa lefutso tsa botenya ka lebaka la khaello ea POMC, LEPR kapa PCSK1 le ho khutlisa botenya bo matla bo qalileng ho tloha liphetohong tsa tsela ea MC4R.
Setmelanotide e sebetsa ho khutlisetsa ts'ebetso ea taolo ea tekanyo ea matla ka ho kenya tšebetsong tsela ea MC4R., ho lebisa ho theolelo ea boima ba 'mele haholo, tlala e fokotsehileng, le ntlafatso ea likarolo tsa metabolic.
2.Taolo ea Mosebetsi oa ho ruruha
Liphuputso tsa Setmelanotide ho li-astrocyte li bontšitse hore e sebetsa ka mokhoa o khethehileng oa ho thibela ho ruruha.
Ka pro-inflammatory cytokine (TNF-α/IFN-γ)- li-astrocyte tse sebetsang, Setmelanotide e ka thibela ka mokhoa o tsotehang ts'ebetso ea NF-κB tsela ea pontšo le ho fokotsa secretion ea pro-inflammatory. lik'hemik'hale (joalo ka CCL2 le CXCL10).
Ntle le ho thibela ho ruruha, Setmelanotide e boetse e etsa hore li-astrocyte li hlahise li-cytokine IL-6 le IL-11 seo se ka kgothaletsa polarization ea macrophage ho ba phenotype e thibelang ho ruruha (Mofuta oa M2).
3.Ntlafatso ea Litšenyehelo tsa Matla
Ho phaella ho fokotsa ho ja lijo ka ho toba (tshebediso), Setmelanotide e boetse e phahamisa litšenyehelo tsa matla a ho phomola (REE).
Ho tšoana le ho phethola switch ea 'mele ea metabolism, ho e nolofalletsa ho chesa lik'hilojule leha u phomotse joalo ka ha eka oa ikoetlisa.
Setmelanotide e hlahisitse keketseho e kholo ho tekanyo ea metabolism ea basal (BMR) le tšebeliso e matla ea matla (AEA) , e lebisang ho fokotseng boima ba 'mele ka potlako mefuteng ea litoeba tse nonneng (mohlala, mohlala oa Magel2-null syndrome).
Sekhahla sa phefumoloho (RER) ho fokotseha hoa liphoofolo ka mora kalafo, e bontshang hore mmele o fetoha ho tloha ho carbohydrate ho ya ho mafura a oxidation, e hlokahalang bakeng sa ho fokotsa sebete le mafura a bolokiloeng.
Ho phomola ha litšenyehelo tsa matla (REE) e ile ea eketseha ka 6.4% le Setmelanotide thutong ea Mokhahlelo oa III mabapi le litaba tsa bophelo bo botle ba botenya, nakong ea phekolo e batlang e le khutšoanyane ea 72 lihora (111 kcal/24 h).
Sena se bolela hore 'mele oa mokuli o chesa lik'hilojule tse eketsehileng, ntle le liphetoho leha e le life lijong.
4.Bophelo bo Botle bo Ntlafetseng ba Metabolic
Setmelanotide ha ea ka ea fokotsa boima ba 'mele feela empa e boetse e bonts'a phetoho ea mafu a amanang le botenya., ho akarelletsa le sebete steatosis le ho hanyetsa insulin.
Phekolo ea Setmelanotide ha e fokotse boima ba 'mele feela, empa hape e fokolitse mafura a sebete, le tshenyo ya sebete.
Sena ha se feela phello ea tahlehelo ea boima ba 'mele empa ke ntlafatso e tobileng mosebetsing oa sebete.
Ka nako e tšoanang, Boemo ba ho itima lijo ho bakuli ba nang le lefu la tsoekere bo ile ba fokotseha haholo ka lebaka la ho fokotseha ha insulin, e bonts'a boemo bo ntlafetseng ba metabolism ea glucose.
Ha mafura a ntse a fokotseha, boemo ba serum ea leptin hape e wele.
Ka kakaretso ho lumeloa hore sena ke sesupo sa bophelo bo botle ba metabolic – kaha maemo a leptin a phahameng haholo hangata a bontša botenya le ho hana insulin.
COA
HPLC
MOF
