I-Sedmelanotide (Igama lomkhiqizo I-Imcivree®) iwukuphuma kwe-octapeptide ye-cyclic kanye nesizukulwane esilandelayo esinamandla futhi siyakhetha I-melanocortin-4 receptor i-agonist. I-melanocortin-4 receptor iyingxenye ebalulekile yesimiso sezinzwa esimaphakathi amandla homeostasis inethiwekhi yokulawula.
I-Setmelanotide iyafana ngesenzo ku okungapheli womuntu i-melanocortin (njenge i-α-melanocyte evuselela i-hormone, α-MSH), kodwa ithuthukiswe ukuthi ibe namandla kakhulu, ekhethiwe futhi izinzile ngokwejwayelekile kunokwemvelo i-ligand.
Ikhombisa phansi kakhulu EC50 (ukugxila okusebenzayo okuyingxenye ephezulu) yakho kokubili umuntu kanye negundane MC4R–0.27 nM kanye 0.28 nM ngokulandelana, ngaleyo ndlela ikhombisa amandla ayo okuvula ama-receptors aphezulu.
I-Setmelanotide yenza kusebenze i-intracellular ikamu ukusayina ngokukhuthazwa kwama-melanocortin-4 receptors akhona ezingxenyeni ezahlukene zobuchopho, kuhlanganise ne i-hypothalamus, ngakho-ke ilawula isifiso sokudla, izindleko zamandla kanye nomsebenzi wezinzwa ezizimele ohlanganisa ukuguqulwa kokulawulwa komfutho wegazi ngokuvuselela ama-preganglionic neurons isimiso sezinzwa esinozwela.
Ngenxa yezakhiwo zayo zokubopha ama-receptors aphezulu, isebenza njengethuluzi elibalulekile lezifundo ze-MC4R-amaprotheni accessory (isib., I-MRAP2) ukusebenzisana.
Ezimweni zomtholampilo, I-Setmelanotide ihunyushwe ngempumelelo yaba umuthi wokwelapha ogxile ekwelapheni izifo ezingavamile zofuzo zokukhuluphala ngokweqile ezitholakala ekushiyekeni kwendlela ye-leptin-melanocortin..
Iphinde ihlehlise ukuzuza kwesisindo okubangelwa izidakamizwa (isib., i-risperidone), ine-anti-inflammatory effects in ama-astrocyte, futhi ingase isebenze ngokuhambisana nokungenelela kwe-metabolic njengalokhu umkhawulo wekhalori-konke okubonisa ukubaluleka kwayo kwesayensi okuphezulu kanye nokusebenza okungaba khona kweminye imikhakha yocwaningo (njengokukhuluphala ngokweqile, i-metabolic syndrome futhi izifo ze-neuroendocrine).
Ukulandelana
I-Ac-Arg-Cys-{d-Ala}-I-His-Phe-Arg-Trp-Cys-NH2 (Ibhuloho le-Disulfide:I-Cys2-Cys8)
Inombolo ye-CAS
920014-72-8
I-Molecular Formula
C₄₉H₆₈N₁₈O₉S₂
Isisindo samangqamuzana
694.91
Ucwaningo lwe-Setmelanotide
1.I-MC4R Pathway kanye ne-MOA ye-Setmelanotide
I-MC4R i I-G protein-coupled receptor (I-GPCR) lokho kuvezwa ikakhulukazi ohlelweni lwezinzwa olumaphakathi, ikakhulukazi ngaphakathi kwama-nuclei ambalwa we-hypothalamus.
Lezi zindawo zimelela amasayithi abalulekile okuzwa izimpawu ze-metabolic kanye nokulawula ukuziphatha kokuphakelayo kanye nokulingana kwamandla.
Ezimweni ze-physiological, le ndlela ye-MC4R ibamba iqhaza ekuvinjweni kwesifiso sokudla kanye nokukhuthazwa kwezindleko zamandla.
Le ndlela ivame ukugqugquzelwa yi-α-melanocyte-stimulating hormone (α-MSH, a I-POMC okuphuma kokunye) ekhiqizwa ama-neurons e-POMC ku- i-nucleus ye-arcuate.
Ukwenziwa kusebenze kwe-MC4R nge-α-MSH kubangela ukugeleza kwezimpawu ezicindezelayo ezicindezela ukudla kanye nokudla..
Kodwa uma kukhona ukuguqulwa kwezakhi zofuzo ze-POMC ezivimbela ukuhlanganiswa kwe-α-MSH, I-MC4R izohlala "ingasebenzi" ngoba ayikutholi noma yikuphi ukuqaliswa ngama-ligand ayo angapheli.
Lokhu kuphazamiseka kwezimpawu kubangela i-pathological, isifiso sokudla esingalawuleki kanye nokukhuluphala ngokweqile okwalandela.
Ukutholwa kwezidakamizwa kumzila we-MC4R bekwaziwa ukuthi kunzima ngaphambi kwe-Setmelanotide.
Ama-agonists angaphambi kwesikhathi angakhethi we-MC4R avuse imiphumela emibi engabekezeleleki efana nokushintsha umbala kwesikhumba kanye nokungasebenzi kahle kwezocansi ngokukhuthaza ezinye. I-melanocortin receptors (i.e., I-MC1R, I-MC3R, kanye ne-MC5R).
Inhloso yokuthuthukiswa kwe-Setmelanotide yayiqondile: ukuthola ukukhetha okuphezulu kwe-MC4R ukuze ithuthukise imiphumela yayo kukho kokubili ukucindezelwa kwesifiso sokudla kanye nokwenyuka kwezindleko zamandla kanye nokunciphisa imiphumela engemihle ehlobene nokubophezela okungekho okuhlosiwe..
Indlela engokwemvelo ewumgogodla we-MC4R agonist yangaphandle i-Setmelanotide iwukusebenza esikhundleni se-α-MSH., ukuvuselela ngokuqondile i-MC4R ukuze kulungiswe i-pathophysiology enhla nomfula futhi ubuyisele lesi siginali ebalulekile yebhalansi yamandla.
Imiphumela yamangqamuzana neselula ye-Setmelanotide ekugcineni ihumushela ekuphenduleni okujulile kwesistimu ye-physiological..
Ngokuvuselela ama-neurons e-MC4R kumasayithi abalulekile kuwo wonke ubuchopho njenge-hypothalamus PVN, I-Setmelanotide iyakwazi:
Izifundo zokukhuluphala ngokweqile kanye ne-Rare Genetic Obesity Syndromes: I-Setmelanotide iyithuluzi elibalulekile ekutadisheni umsebenzi womzila we-MC4R.
Ngokuphawulekayo, kuboniswe ukuthi kusebenza ngempumelelo ekwelapheni izinhlobo zofuzo ezingavamile zokukhuluphala ngenxa yokuntuleka kwe-POMC, I-LEPR noma I-PCSK1 futhi uhlehlise ukukhuluphala kwangaphambi kwesikhathi okungathi sína kusuka ezinguqukweni zendlela ye-MC4R.
I-Setmelanotide yenza ukubuyisela umsebenzi wokulawula ibhalansi yamandla ngokwenza kusebenze indlela ye-MC4R, okuholela ekwehleni kwesisindo esikhulu, yehla indlala, kanye nokuthuthukiswa kwemingcele ye-metabolic.
2.Ukulawulwa Komsebenzi Wokuvuvukala
Ucwaningo lwe-Setmelanotide kuma-astrocyte lubonise ukuthi lusebenza umsebenzi okhethekile wokulwa nokuvuvukala.
Ku-pro-inflammatory i-cytokine (TNF-α/IFN-γ)- ama-astrocyte acushiwe, I-Setmelanotide ingacindezela ngokuphawulekayo ukusebenza kwendlela yokusayina ye-NF-κB futhi yehlise ukugcinwa kwe-pro-inflammatory. amakhemikhali (njenge CCL2 futhi CXCL10).
Ngaphandle kokuvinjelwa kokuvuvukala, I-Setmelanotide futhi yenza ama-astrocyte akhiphe ama-cytokines I-IL-6 futhi I-IL-11 lokho kungakhuthaza i-macrophage polarization ibe yi-phenotype elwa nokuvuvukala (Uhlobo lwe-M2).
3.Ukuthuthukiswa Kwezindleko Zamandla
Ngaphezu kokunciphisa ngokuqondile ukudla (ukusetshenziswa), I-Setmelanotide iphinde inyuse izindleko zamandla okuphumula (REE).
Kufana nokushintshashintsha kwe-metabolic emzimbeni, ukuyivumela ukuthi ishise ama-calories ngisho uphumule njengokungathi uyajima.
I-Setmelanotide ikhiqize ukwanda okukhulu ku isilinganiso se-basal metabolic (I-BMR) kanye nezindleko zamandla asebenzayo (I-AEA) , okuholela ekwehliseni isisindo ngokushesha kumamodeli wamagundane akhuluphele (isib., imodeli ye-Magel2-null syndrome).
I-quotient yokuphefumula (I-RER) kuncipha ezilwaneni ngemva kokwelashwa, okubonisa ukuthi umzimba uyashintsha usuka kuma-carbohydrate uye ku-fat oxidation, okudingekayo ekuqedeni isibindi namafutha agciniwe.
Ukuphumula kwezindleko zamandla (REE) yanda ngo 6.4% nge-Setmelanotide ocwaningweni lweSigaba III ngezihloko ezinempilo ezikhuluphele, ngesikhathi sokwelashwa esifushane uma kuqhathaniswa 72 amahora (111 kcal/24 h).
Lokhu kusho ukuthi umzimba wesiguli ushisa ama-calorie engeziwe, ngaphandle kwezinguquko ekudleni.
4.Impilo Ye-Metabolic Ethuthukisiwe
I-Setmelanotide ayizange nje ibangele ukuncipha kwesisindo kodwa futhi ibonise ukuguqulwa kwezifo ezihlobene nokukhuluphala ngokweqile., kufaka phakathi i-hepatic steatosis kanye ukumelana ne-insulin.
Ukwelashwa kwe-Setmelanotide akugcini nje ukunciphisa isisindo, kodwa futhi kunciphise okuqukethwe kwamafutha esibindi, kanye nokulimala kwesibindi.
Lokhu akuwona nje umphumela wokuncipha kwesisindo kodwa kuwukuthuthuka okuqondile ekusebenzeni kwesibindi.
Ngokuhambisanayo, Izinga lokuzila ukudla kwe-insulin ezigulini lehla ngokuphawulekayo ngokunciphisa ukumelana ne-insulin, kukhombisa isimo esithuthukisiwe se-glucose metabolism.
Lapho amafutha ehla, amazinga e-serum i-leptin nayo yawa.
Lokhu ngokuvamile kukholakala ukuthi kuyinkomba yempilo engcono ye-metabolic – njengoba amazinga e-leptin ephakeme kakhulu evamise ukukhombisa ukukhuluphala kanye nokumelana ne-insulin.
I-COA
I-HPLC
MS
