Compound monograph
Setmelanotide
Setmelanotide is a synthetic disulfide-cyclized octapeptide characterised as an MC4R-preferring melanocortin receptor agonist.
01
Identity & nomenclature
Setmelanotide is a synthetic disulfide-cyclized octapeptide characterised as an MC4R-preferring melanocortin receptor agonist.
'Cyclic melanocortin' does not identify the cyclization chemistry. A disulfide ring and a side-chain lactam are different molecules with different stability and different analytical handling, and a linear sequence with the word cyclic appended describes neither.
Declared aliases and development codes: RM-493, BIM-22493, IRC-022493.
02
Molecular properties
| Molecular formula | C49H68N18O9S2 |
|---|---|
| Molecular mass | 1117.32 Da |
| CAS Registry Number | 920014-72-8 |
| PubChem CID | 11993702 |
| UNII | N7T15V1FUY |
| Three-letter sequence | Ac–Arg–Cys–D-Ala–His–D-Phe–Arg–Trp–Cys–NH2 |
Eight residues closed by a Cys2-Cys8 DISULFIDE. No linear string is published here. This is not a head-to-tail ring and not an Asp-Lys lactam — the distinction from the Melanotan II scaffold is the point of the entry.
03
Structural characteristics
A cryo-EM structure of the setmelanotide-bound MC4R signalling complex reveals the activation switch, and reports that calcium is required for agonist but not antagonist activity — the same cofactor identified in the antagonist-bound structure of the same receptor. MC4R-preferring should not be upgraded to MC4R-exclusive, and no assay-independent subtype-selectivity or signalling-bias value is established.
- Cys2-Cys8 intramolecular disulfide
- D-Ala3
- D-Phe5
Terminal features: N-terminal acetylation at Arg1, C-terminal amide at Cys8.
04
Molecular targets & mechanisms
05
Analytical considerations
Combine intact high-resolution MS with sequence analysis and a reducing versus nonreducing comparison; reduction of the single intramolecular disulfide adds 2.0157 Da before alkylation. Verify Cys2-Cys8 connectivity specifically and exclude intermolecular disulfide dimers, which share the monomer's amino-acid composition. D-Ala3 and D-Phe5 need a stereochemical method; neither a mass match nor an area-purity figure addresses them.
06
Verified bibliography
- Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.current
Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M
Science (New York, N.Y.) · 2021-04-15 · Journal Article
- Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.current
Heyder NA, Kleinau G, Speck D, Schmidt A, Zschunke S, Szczepek M, Bauer B, Koch A, Gallandi M, Kwiatkowski D, Bürger J, Mielke T, Beck-Sickinger AG, Hildebrand PW, Spahn CMT, Hilger D, Schacherl M, Biebermann H, Hilal T, Kühnen P, Kobilka BK, Scheerer P
Cell research · 2021-09-24 · Journal Article
- Structural insights into ligand recognition and activation of the melanocortin-4 receptor.current
Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y
Cell research · 2021-08-25 · Journal Article
10
Methodology & citation verification
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