Sedmelanotide (aha ika Imcivree®) bụ ihe mgbapụta octapeptide cyclic yana ọgbọ na-abịa nke nwere ike na nhọrọ melanocortin-4 nnabata agonist. Ihe nnabata melanocortin-4 bụ akụkụ dị mkpa nke sistemu ụjọ etiti ike homeostasis netwọk iwu.
Setmelanotide yiri n'omume endogenous mmadu melanocortins (dị ka α-melanocyte hormone na-akpali akpali, α-MSH), mana emelitere ka ọ bụrụ nnukwu ike karịa, nhọrọ na metabolically kwụsie ike karịa eke ligand.
Ọ na-egosi oke ala EC50 (ọkara kacha dị irè mkpokọta) maka ma mmadụ na oke MC4R-0.27 nM na 0.28 nM n'otu n'otu, si otú ahụ na-egosipụta nnukwu ike nnabata nnabata ya.
Setmelanotide na-arụ ọrụ intracellular cAMP na-egosi site na mkpali nke ndị na-anabata melanocortin-4 dị n'akụkụ dị iche iche nke ụbụrụ, gụnyere ndị hypothalamus, ya mere na-achịkwa agụụ, mmefu ike na ọrụ akwara autonomic gụnyere mgbanwe nke njikwa ọbara mgbali site na-akpali akpali neurons nke preganglionic. usoro ụjọ ụjọ.
N'ihi na ya elu anabata njide Njirimara, ọ na-eje ozi dị ka ngwá ọrụ bara uru maka ọmụmụ nke MC4R-ngwa na-edozi ahụ (eg., MRAP2) mmekọrịta.
Na ntọala ụlọ ọgwụ, Asụgharịla Setmelanotide nke ọma ka ọ bụrụ ọgwụ ọgwụgwọ lekwasịrị anya n'ịgwọ ọrịa oke ibu mkpụrụ ndụ ihe nketa na-enweta site na ntụpọ dị na ụzọ leptin-melanocortin..
Ọ na-agbanwekwa ibu ibu ọgwụ na-ebute (eg., risperidone), nwere mmetụta mgbochi mkpali na astrocytes, ma nwee ike na-emekọ ihe ọnụ na mmemme metabolic dị ka mmachi caloric- ihe niile na-egosipụta uru sayensị dị elu yana ike itinye ya na mpaghara nyocha ndị ọzọ (dị ka oke ibu, metabolic syndrome na ọrịa neuroendocrine).
Usoro
Ac-Arg-Cys-{d-Ala}-His-Phe-Arg-Trp-Cys-NH2 (Disulfide akwa:Cys2-Cys8)
Nọmba CAS
920014-72-8
Usoro ihe omimi
C₄₉H₆₈N₁₈O₉S₂
Ibu molekụla
694.91
Nnyocha nke Setmelanotide
1.Ụzọ MC4R na MOA nke Setmelanotide
MC4R bụ a G na-anabata protein jikọtara ọnụ (GPCR) nke a na-egosipụta nke ọma na sistemu ụjọ nke etiti, karịsịa n'ime obere oghere nke hypothalamus.
Mpaghara ndị a na-anọchite anya saịtị ndị bụ isi maka ịmata ihe mgbakasị ahụ na ịchịkwa omume nri na nguzozi ike.
Na physiological ọnọdụ, Ụzọ MC4R a na-ekere òkè na mgbochi nke agụụ na mkpali nke mmefu ume..
Ụzọ a na-ejikarị α-melanocyte na-akpali akpali (α-MSH, a POMC ewepụtara) nke POMC neurons mepụtara na arcuate nucleus.
Nkwalite MC4R site na α-MSH na-ebute oke mgbama mgbada na-egbochi agụụ na iri nri..
Mana ọ bụrụ na enwere mmụgharị na mkpụrụ ndụ POMC nke na-egbochi njikọ α-MSH, MC4R ga-anọgide "na-adịghị arụ ọrụ" n'ihi na ọ naghị enweta ọrụ ọ bụla site na ligands endogenous ya..
Ihe mgbaàmà a na-ebute ọrịa pathological, agụụ na-achịkwaghị achịkwa na oke ibu ọrịa na-esochi.
Nchọpụta ọgwụ maka ụzọ MC4R siri ike nke ọma tupu Setmelanotide.
Ndị agonists MC4R na-abụghị ndị mbụ kpalitere mmetụta ọjọọ na-enweghị ike ịnagide dị ka pigmenti anụ ahụ na arụrụ ọrụ mmekọahụ site na-akpali akpali ndị ọzọ. ndị na-anabata melanocortin (ya bụ., MC1R, MC3R, na MC5R).
Ebumnuche mmepe nke Setmelanotide kwụ ọtọ: iji nweta oke nhọrọ maka MC4R iji bulie mmetụta ya na ma nbibi agụụ na ụbara mmefu ike yana belata mmetụta ndị metụtara na-ejikọta ihe na-apụ apụ..
Isi ihe dị n'ime ya nke exogenous MC4R agonist Setmelanotide bụ iji dochie anya α-MSH., na-akpali akpali MC4R ozugbo iji mezie pathophysiology elu ma weghachi akara ngosi a dị oke egwu maka nguzozi ike..
Mmetụta molekụla na cellular nke Setmelanotide na-atụgharị n'ikpeazụ na nzaghachi physiological siri ike..
Site na-akpali neurons MC4R na saịtị dị mkpa na ụbụrụ ụbụrụ dịka hypothalamus PVN., Setmelanotide nwere ike:
Ihe omumu ihe omumu nke oke ibu na oke ibu na genetic oke ibu: Setmelanotide bụ ngwá ọrụ dị mkpa n'ịmụ ọrụ nke ụzọ MC4R.
Karịsịa, egosila na ọ dị irè n'ịgwọ ụdị oke ibu nke mkpụrụ ndụ ihe nketa na-adịghị ahụkebe n'ihi ụkọ POMC., LEPR ma ọ bụ PCSK1 ma tụgharịa oke oke ibu mmalite mmalite site na mmụpụta n'ụzọ MC4R.
Setmelanotide na-arụ ọrụ iji weghachi ọrụ nke nhazi nguzozi ike site na ịgbalite ụzọ MC4R., na-eduga nnukwu ibu ibu, belata agụụ, na mmụba nke paramita metabolic.
2.Iwu nke ọrụ mbufụt
Nnyocha nke Setmelanotide na astrocytes egosila na ọ na-arụ ọrụ mgbochi mkpali pụrụ iche.
Na pro-inflammatory cytokine (TNF-a/IFN-γ)- astrocytes na-arụ ọrụ, Setmelanotide nwere ike igbochi mmalite nke ụzọ akara NF-κB ma belata nzuzo nke pro-inflammatory. chemokines (dị ka CCL2 na CXCL10).
Ewezuga mgbochi nke mbufụt, Setmelanotide na-akpalikwa astrocytes na-ezobe cytokines IL-6 na IL-11 nke nwere ike ịkwalite macrophage polarization n'ime ihe mgbochi mkpali phenotype (Ụdị M2).
3.Mmefu ume ike
Na mgbakwunye na ibelata nri nri ozugbo (oriri), Setmelanotide na-ebulikwa mmefu ike izu ike (REE).
Ọ dị ka ịtụgharị na mgba ọkụ nke anụ ahụ, na-enyere ya aka ịkụ calorie ọbụna na-ezu ike dị ka a ga-asị na ọ na-emega ahụ.
Setmelanotide mepụtara nnukwu mmụba na ya basal metabolic ọnụego (BMR) na mmefu ike na-arụ ọrụ (AEA) , na-eduga ngwa ngwa mbelata ibu ibu ụdị òké (eg., Ụdị ọrịa Magel2-null syndrome).
Ọnụ ọgụgụ nke iku ume (RER) mbelata na ụmụ anụmanụ mgbe ọgwụgwọ, nke na-egosi na ahụ na-agbanwe site na carbohydrate gaa na abụba oxidation, dị mkpa maka imeju imeju na abụba echekwara.
Mmefu ume ezumike (REE) e mụbara site 6.4% ya na Setmelanotide n'ọmụmụ ihe nke atọ na isiokwu ndị nwere oke ibu, n'oge a dịtụ mkpirikpi ọgwụgwọ oge nke 72 awa (111 kcal/24 h).
Nke a pụtara na ahụ onye ọrịa na-ere calorie ndị ọzọ, na-enweghị mgbanwe ọ bụla na nri.
4.Ahụike Metabolic emelitere
Setmelanotide ọ bụghị naanị butere oke ibu mana ọ gosipụtara ngbanwe nke ọrịa metabolic metụtara oke ibu., gụnyere ịba ọcha n'anya steatosis na insulin iguzogide.
Ọgwụ Setmelanotide abụghị naanị ibelata ibu, ma belatakwa abụba imeju, na mmebi imeju.
Nke a abụghị naanị mmetụta nke mbelata ibu mana ọ bụ nkwalite kpọmkwem na ọrụ imeju.
N'otu oge, Insulin nke ndị ọrịa na-ebu ọnụ na-ebelata nke ọma site na mmụba nke nguzogide insulin, na-egosipụta ọnọdụ nke glucose metabolism ka mma.
Mgbe oke abụba jụrụ, ọkwa nke serum leptin dakwara.
A na-ekwenyekarị na nke a bụ ihe na-egosi ahụike metabolic ka mma – Ebe ọ bụ na ọkwa leptin dị elu na-egosikarị oke ibu na nguzogide insulin.
COA
HPLC
MS
