Sedmelanotide (Dzina lachidziwitso Imcivree®) ndi chochokera ku cyclic octapeptide ndi m'badwo wotsatira wamphamvu komanso wosankha melanocortin-4 cholandilira agonist. Cholandilira cha melanocortin-4 ndi gawo lofunikira la dongosolo lapakati lamanjenje mphamvu homeostasis malamulo network.
Setmelanotide ndi yofanana ndi kuchitapo kanthu amkati munthu melanocortins (monga α-melanocyte stimulating hormone, α-MSH), koma yapangidwa kuti ikhale yamphamvu kwambiri, kusankha ndi kagayidwe wokhazikika kuposa zachilengedwe ligandi.
Zikuwonetsa zotsika kwambiri EC50 (theka-pazikulu ogwira ndende) kwa anthu ndi makoswe MC4R–0.27 nM ndi 0.28 nM motsatira, potero kuwonetsa mphamvu yake yayikulu yolumikizira ma receptor.
Setmelanotide imayendetsa ma intracellular CAMP kuwonetsa kudzera pakukondoweza kwa melanocortin-4 zolandilira zomwe zimapezeka m'malo osiyanasiyana a ubongo, kuphatikizapo hypothalamus, motero amawongolera chilakolako, kugwiritsa ntchito mphamvu ndi zochita zamanjenje zodziyimira pawokha kuphatikiza kusinthasintha kwa kuthamanga kwa magazi polimbikitsa ma preganglionic neurons a dongosolo lamanjenje lachifundo.
Chifukwa champhamvu zake zomangira ma receptor, imagwira ntchito ngati chida chofunikira pamaphunziro a MC4R-zowonjezera mapuloteni (mwachitsanzo, MRAP2) kuyanjana.
M'malo azachipatala, Setmelanotide yamasuliridwa bwino kukhala mankhwala achire omwe amayang'ana kwambiri pochiza matenda osowa kunenepa kwambiri omwe amachokera ku zolakwika mu njira ya leptin-melanocortin..
Imabwezeretsanso kunenepa koyambitsidwa ndi mankhwala (mwachitsanzo, risperidone), ali ndi anti-inflammatory effect astrocytes, ndipo amatha kuchita mogwirizana ndi njira za metabolic monga kuchepetsa caloric-zonsezi zikuwonetsa kufunikira kwake kwasayansi komanso kuthekera kwake m'magawo ena ofufuza (monga kunenepa kwambiri, metabolic syndrome ndi matenda a neuroendocrine).
Kutsatizana
Ac-Arg-Cys-{d-Ala}-His-Phe-Arg-Trp-Cys-NH2 (Disulfide mlatho:Cys2-Cys8)
Nambala ya CAS
920014-72-8
Molecular Formula
C₄₉H₆₈N₁₈O₉S₂
Kulemera kwa Maselo
694.91
Kafukufuku wa Setmelanotide
1.MC4R Pathway ndi MOA ya Setmelanotide
MC4R ndi G protein-coupled receptor (GPCR) zomwe zimawonetsedwa makamaka mu dongosolo lapakati lamanjenje, makamaka mkati mwa minyewa yochepa ya hypothalamus.
Madera awa akuyimira malo ofunikira kuti azitha kuzindikira zizindikiro za metabolic ndikuwongolera machitidwe odyetsera komanso mphamvu zamagetsi.
Mu zokhudza thupi zikhalidwe, njira iyi ya MC4R imatenga nawo gawo pakuletsa kudya komanso kulimbikitsa kugwiritsa ntchito mphamvu..
Njira imeneyi nthawi zambiri imalimbikitsidwa ndi α-melanocyte-stimulating hormone (α-MSH, a POMC zochokera) opangidwa ndi POMC neurons mu phata la arcuate.
Kutsegula kwa MC4R ndi α-MSH kumapangitsa kutsika kwa ma siginecha akumunsi omwe amalepheretsa kudya komanso kudya..
Koma ngati pali masinthidwe mu jini ya POMC yomwe imalepheretsa kaphatikizidwe ka α-MSH, MC4R ikhalabe "yosagwira ntchito" chifukwa sichilandira kutsegulidwa ndi ma ligand ake.
Kusokonezeka kwa chizindikiro ichi kumabweretsa pathological, chilakolako chosalamulirika komanso kunenepa kwambiri.
Kupeza mankhwala kwa njira ya MC4R kunali kovuta kwambiri pamaso pa Setmelanotide.
Ma agonists oyambilira osasankha a MC4R adadzetsa mavuto osaneneka monga kutulutsa khungu komanso kusagwira bwino ntchito pakugonana polimbikitsa ena. melanocortin receptors (i.e., Chithunzi cha MC1R, Chithunzi cha MC3R, ndi MC5R).
Cholinga cha chitukuko cha Setmelanotide chinali cholunjika: kuti mukwaniritse kusankha kwakukulu kwa MC4R kukhathamiritsa zotsatira zake pakuchepetsa chilakolako komanso kuchuluka kwa ndalama zogwiritsira ntchito mphamvu ndikuchepetsa zotsatira zoyipa zokhudzana ndi zomwe mukufuna..
Makina oyambira a exogenous MC4R agonist Setmelanotide ndikulowa m'malo mwa α-MSH., kulimbikitsa mwachindunji MC4R kuti akonze matenda a pathophysiology kumtunda ndikubwezeretsa chizindikiro chofunikira ichi cha mphamvu zamagetsi..
Zotsatira za ma cell ndi ma cell a Setmelanotide pamapeto pake zimamasulira kukhala mayankho ozama amthupi..
Polimbikitsa ma neuron a MC4R pamalo ofunikira muubongo wonse monga hypothalamus PVN, Setmelanotide imatha:
Maphunziro a Kunenepa Kwambiri ndi Osowa Kunenepa Kwambiri pa Genetic Obesity Syndromes: Setmelanotide ndi chida chofunikira powerenga ntchito ya njira ya MC4R.
Zowonjezereka, zasonyezedwa kuti ndizothandiza pochiza mitundu yachilendo ya kunenepa kwambiri chifukwa cha kusowa kwa POMC, LEPR kapena PCSK1 ndikusintha kunenepa koyambilira koyambirira kuchokera ku masinthidwe amtundu wa MC4R.
Setmelanotide imachita kuti ibwezeretse magwiridwe antchito a mphamvu zamagetsi poyambitsa njira ya MC4R., kumabweretsa kuwonda kwambiri, njala inachepa, ndi kusintha kwa magawo a metabolic.
2.Kuwongolera Ntchito Yotupa
Kafukufuku wa Setmelanotide mu astrocytes awonetsa kuti amagwira ntchito yapadera yoletsa kutupa.
Mu pro-inflammatory cytokine (TNF-α/IFN-γ)- ma astrocyte opangidwa, Setmelanotide imatha kupondereza kwambiri kuyambitsa kwa NF-κB njira yolumikizira ndikuchepetsa kutulutsa kwa pro-inflammatory. mankhwala a chemokines (monga Mtengo wa CCL2 ndi Chithunzi cha CXCL10).
Kupatula kuletsa kutupa, Setmelanotide imapangitsanso ma astrocyte kuti atulutse ma cytokines IL-6 ndi IL-11 zomwe zingalimbikitse macrophage polarization mu anti-inflammatory phenotype (M2 mtundu).
3.Kuwongola Ndalama Zamagetsi
Kuwonjezera mwachindunji kuchepetsa kudya (kumwa), Setmelanotide imakwezanso ndalama zopumira (REE).
Zili ngati kutembenuka pakusintha kwa metabolic m'thupi, kupangitsa kuti aziwotcha zopatsa mphamvu ngakhale pakupuma ngati akuchita masewera olimbitsa thupi.
Setmelanotide idapanga kuwonjezeka kwakukulu mu basal metabolic rate (BMR) komanso kugwiritsa ntchito mphamvu zamagetsi (AEA) , kumabweretsa kutsika kwachangu kwa mbewa zonenepa kwambiri (mwachitsanzo, mtundu wa Magel2-null syndrome).
The kupuma quotient (RER) amachepetsa nyama pambuyo mankhwala, zomwe zimasonyeza kuti thupi limasintha kuchoka ku carbohydrate kupita ku mafuta oxidation, zofunika kuchepetsa chiwindi ndi kusungidwa mafuta.
Kupumula kwa ndalama zamagetsi (REE) yawonjezeka ndi 6.4% ndi Setmelanotide mu kafukufuku wa Gawo III pa maphunziro athanzi onenepa, pa nthawi yochepa mankhwala nthawi ya 72 maola (111 kcal / 24h).
Izi zikutanthauza kuti thupi la wodwalayo likuwotcha ma calories owonjezera, popanda kusintha kulikonse kwa zakudya.
4.Thanzi labwino la Metabolic
Setmelanotide sinangowonjezera kuwonda koma idawonetsanso kusintha kwa matenda okhudzana ndi kunenepa kwambiri., kuphatikizapo hepatic steatosis ndi kukana insulini.
Setmelanotide mankhwala osati kuchepetsa kulemera, komanso kuchepetsa mafuta a chiwindi, ndi kuwonongeka kwa chiwindi.
Izi sizongokhudza kuchepa thupi koma ndizowonjezera mwachindunji mu chiwindi.
Concomitant, Kusala kudya kwa odwala omwe ali ndi matenda a shuga a mtundu wachiwiri kumachepetsa kwambiri kukana kwa insulin, kuwonetsa kusintha kwa glucose metabolism.
Pamene mafuta akuchepa, mlingo wa seramu leptin nawonso adagwa.
Izi nthawi zambiri amakhulupirira kuti ndi chizindikiro cha thanzi labwino la metabolic – popeza milingo ya leptin yokwera kwambiri nthawi zambiri imawonetsa kunenepa kwambiri komanso kukana insulini.
COA
Mtengo wa HPLC
MS
