Setmelanotide 10mg/1ml solution for injection vials

Grehlin and other hunger signals from the gastrointestinal tract stimulate orexigenic neurons, stimulating the release of agouti-related protein.[A224459] Agouti-related protein inhibits melanocortin 4 receptor (MC4R) activation until satiety signals such as insulin or leptin stimulate anorexigenic neurons.[A224459] Insulin and leptin stimulate production of the POMC-derived melanocortin peptide α-melanocyte simulating hormone, which is a ligand of MC4R.[A224459][A224449]

Orexigenic and anorexigenic neurons contain prohormone convertase 1/3 (PC1/3), which is encoded by the gene proprotein subtilisin/kexin type 1.[A224464] PC1/3 preforms activation cleavage of a number of peptide hormone precursors, including α-melanocyte simulating hormone.[A224464]

Setmelanotide is a pro-opiomelanocortin derived peptide that is an agonist of MC4R.[A224449] It is an approximately 20-fold more potent agonist of MC4R than endogenous α-melanocyte stimulating hormone, with an EC₅₀ of 0.27 nM.[A224459][A224449] By directly agonizing MC4R, upstream genetic deficiencies in the MC4R signalling pathway cannot inhibit satiety, food intake is decreased, and weight loss is achieved.[A224449][A224459][A224464]

MC4R is a 332 amino acid G-protein coupled receptor (G-PCR).[A224459] Although the lack of cardiovascular adverse effects with setmelanotide treatment are not well understood, it is believed that earlier MC4R antagonists activated multiple G-protein signalling pathways.[A224449] Earlier drugs that targeted G-PCRs either bound with high affinity to the highly conserved orthosteric binding site, or with high specificity to less conserved allosteric sites.[A224459] Setmelanotide is an atypical bitopic ligand that interacts with both the orthosteric and putative allosteric binding site, allowing for both high affinity and specificity.[A224459]