Compound monograph
Setmelanotide
Setmelanotide is a synthetic disulfide-cyclized octapeptide characterised as an MC4R-preferring melanocortin receptor agonist. A review by Swan et al. (PMID 38834138) describes setmelanotide as an analogue of alpha-melanocyte-stimulating hormone; that is a review-level parent attribution, not a residue-by-residue design account.
01
Identity & nomenclature
Setmelanotide is a synthetic disulfide-cyclized octapeptide characterised as an MC4R-preferring melanocortin receptor agonist. A review by Swan et al. (PMID 38834138) describes setmelanotide as an analogue of alpha-melanocyte-stimulating hormone; that is a review-level parent attribution, not a residue-by-residue design account.
'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 | Arg–Cys–D-Ala–His–D-Phe–Arg–Trp–Cys |
| Terminal groups | N-terminal acetylation at Arg1; C-terminal amide at Cys8 |
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. Gary et al. (PMID 39394922) describe setmelanotide as cyclized by a disulfide bond formed through its two cysteine residues, here Cys2 and Cys8.
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
Ring closures: covalent bonds between residues, by position counted from the first residue of the chain.
- Disulfide Cys2–Cys8: thiol sulfur (Sγ) to thiol sulfur (Sγ). Source: PMID 39394922.
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.
Disagreements and mix-ups
Points where sources disagree about this compound's identity, or where a name or form is easily confused with another, as noted in this record. The discrepancy register quotes the passage for each one.
Often mixed up · Name or substance
Disulfide ring vs lactam ring in cyclic melanocortin peptides
What the studies reported
Each finding describes one cited study in its stated model. These observations are specific to that study and do not establish effects in other settings.
Cell and tissue studies
Human MC4R-Gs cryo-electron microscopy preparation
Using a human MC4R-Gs cryo-electron microscopy preparation, the study reported a setmelanotide-bound signaling complex.
Reference [1]Human MC4R-Gs setmelanotide-bound complex and functional analysis
Using a human MC4R-Gs setmelanotide-bound complex and functional analysis, the study reported a requirement for calcium in agonist activity.
Reference [1]MC4R-Gs cryo-electron microscopy preparation
Using an MC4R-Gs cryo-electron microscopy preparation, the study reported the setmelanotide-bound complex at 2.6 Å resolution.
Reference [2]MC4R-Gs structural preparations and structure-derived mutant signaling assays
Using MC4R-Gs structural preparations and structure-derived mutant signaling assays, the study identified TM3 interactions and calcium ion as features of setmelanotide ligand recognition.
Reference [2]
06
Verified bibliography
Cited studies by type
The 5 papers this record cites, counted by the kind of work each reports. A count is the size of this record's selection, not of the research that exists, and says nothing about results, safety, effectiveness or approval.
A paper can report more than one kind of work. Each count opens those papers in the bibliography. Compare every record on the Evidence Map.
Reference 1
Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.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
currentReference 2
Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.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
currentReference 3
Structural insights into ligand recognition and activation of the melanocortin-4 receptor.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
currentReference 4
Harnessing the melanocortin system in the control of food intake and glucose homeostasis.Swan P, Johnson B, le Roux CW, Miras AD
Peptides · 2024-06-02 · Review
currentReference 5
Carbocyclic setmelanotide analogs maintain biochemical potency at melanocortin 4 receptors.Gary S, Roy A, Bloom S
Journal of peptide science : an official publication of the European Peptide Society · 2024-10-12 · Journal Article
current
Study models of these references
What kind of experiment each cited paper reports, taken from its abstract unless marked. Not a summary of results.
| Reference | Study models |
|---|---|
| Israeli H et al. 2021 | Study models reported: in vitro · from the abstract |
| Heyder NA et al. 2021 | Study models reported: in vitro · from the abstract |
| Zhang H et al. 2021 | Study models reported: in vitro · from the abstract |
| Swan P et al. 2024 | Review article |
| Gary S et al. 2024 | Study models reported: in vitro · from the abstract |
Record history
Published 2026-09-13.
- : Sequence and structure
- : Identity and nomenclature, Sequence and structure, References
Each entry names the parts of this record that changed on that date. Changes to links between records and to catalogue links are not listed. This history covers the tracked record fields; study findings are not listed here.
Cite this record: Purely Peptides Research Library. Setmelanotide. Published 2026-09-13; updated 2026-10-15. https://purelypeptides.org/research/compounds/setmelanotide/
10
Methodology & citation verification
Reference identity is checked against official PubMed metadata. Local deterministic receipts bind each normalized title and canonical metadata record to its verification date. Scientific values remain absent when an authoritative source has not been verified.
Read the full methodology →