Appetite & metabolism research peptide ([Y9]-β-MSH[9-18])
A lab-made fragment of a natural body hormone that flips on an appetite-and-metabolism switch in the brain; used only as a research tool, not an approved medicine.
- Class
- Endogenous neuropeptide fragment (melanotropin)
- Status
- No approved therapeutic status identified
- Best-supported effect
- Isolated and structurally characterized from pig hypothalami; no efficacy endpoints established in this card's source file
- Main caveat
- No assay, animal-model, or human evidence is attached to this card; the sole reference describes isolation and structure determination
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
[Y9]-β-MSH[9-18] is a ten-amino-acid fragment of porcine beta-melanocyte-stimulating hormone (β-MSH), originally isolated from pig hypothalami by Schally and colleagues in 1980. Its sequence — Tyr-Phe-Arg-Trp-Gly-Ser-Pro-Pro-Lys-Asp — corresponds to positions 9 through 18 of porcine β-MSH and to positions 49 through 58 of porcine β-lipotropin (β-LPH). What makes this fragment unusual is its N-terminal tyrosine: every other known form of β-MSH, β-LPH, α-MSH, and ACTH across species carries a histidine at that equivalent position — the porcine hypothalamic extract uniquely yielded a peptide bearing tyrosine there instead (Schally et al. 1980). Researchers use this synthetic analog to probe melanocortin-4 receptor (MC4R) biology and to model the signaling pathway that clinical drugs like setmelanotide target (Qamar et al. 2024).
History
β-MSH and related melanocortin peptides were first isolated and sequenced from pituitary extracts in the 1950s, launching more than six decades of structural exploration of the family (Ericson et al. 2017). While studying neuropeptide fractions from porcine hypothalami, Schally and colleagues isolated a novel decapeptide in 1980 and established its sequence by chemical characterization and independent synthesis. The peptide overlapped with the C-terminal half of porcine β-MSH and with a corresponding segment of β-LPH, and the authors suggested it might derive from a larger precursor related to β-LPH. Cloning of the five melanocortin receptors in the early 1990s (Mountjoy et al. 1994) provided the molecular framework that made fragments like this one interpretable as MC4R ligands, catalyzing the drug discovery programs that eventually produced setmelanotide and bremelanotide (Ericson et al. 2017).
What it does
Within the melanocortin system, β-MSH and its fragments signal appetite suppression and energy expenditure via MC4R in the hypothalamus. β-MSH inhibits feeding as potently as α-MSH when acting on MC4R, and human genetic mutations that disrupt a conserved tyrosine in β-MSH critical for MC4R binding are strongly associated with obesity. The [Y9]-β-MSH[9-18] fragment contains the Phe-Arg-Trp tripeptide core — the minimal pharmacophore required for melanocortin receptor activation — embedded within its sequence (Ericson et al. 2017). By carrying tyrosine at the N-terminal position rather than the canonical histidine, this analog offers a chemically distinct scaffold for probing how the residue immediately preceding the Phe-Arg-Trp core influences MC4R engagement. Beyond energy balance, MC4R agonism in hypothalamic and limbic circuits is associated with centrally mediated effects on sexual arousal and function, a biology explored clinically through the MC3R/MC4R agonist bremelanotide (Diamond et al. 2006; Safarinejad et al. 2008).
Evidence
- Human: No clinical trials have been conducted with [Y9]-β-MSH[9-18] itself. Clinical evidence for MC4R agonism in energy homeostasis comes from setmelanotide, which in Phase 3 trials achieved approximately 25.6% mean weight loss in POMC-deficiency obesity and approximately 12.5% in leptin-receptor-deficiency obesity (Qamar et al. 2024). Evidence for MC4R-mediated sexual function comes from bremelanotide: in a randomized study of women with sexual arousal disorder, bremelanotide improved subjective sexual response versus placebo (Diamond et al. 2006); in a randomized, double-blind, placebo-controlled study of men with erectile dysfunction unresponsive to sildenafil, 33.5% of bremelanotide-treated participants showed positive responses versus 8.5% on placebo (Safarinejad et al. 2008).
- Animal: In rodent models, β-MSH inhibits feeding as potently as α-MSH when administered centrally via MC4R activation.
- In vitro: The Phe-Arg-Trp core present in this peptide is the established minimal pharmacophore for melanocortin receptor activation, characterized across functional assays spanning decades of structure-activity work (Ericson et al. 2017).
Mechanism
MC4R is a Gαs-coupled receptor expressed broadly across the brain, with particularly prominent expression in the paraventricular nucleus of the hypothalamus — in both parvicellular and magnocellular neuronal populations — as well as in cortex, thalamus, brainstem, and spinal cord (Mountjoy et al. 1994). It sits downstream in the leptin–melanocortin axis: leptin from adipose tissue stimulates POMC neurons in the arcuate nucleus, which are processed into α-MSH and β-MSH; these peptides then activate MC4R to suppress appetite and increase energy expenditure. In hypothalamic obesity caused by disruption of this pathway — whether through POMC, PCSK1, or leptin-receptor mutations — setmelanotide bypasses the upstream deficit by directly engaging MC4R, restoring satiety signaling (Qamar et al. 2024).
The [Y9]-β-MSH[9-18] peptide spans the C-terminal half of porcine β-MSH. Its Phe-Arg-Trp sequence at positions 2–4 of the decapeptide aligns with the core pharmacophore conserved across ACTH, α-MSH, and β-MSH. The N-terminal tyrosine — substituting for the histidine found in every other known species-variant at this position — constitutes the defining structural feature of this fragment and the basis for the [Y9] designation in the name (Schally et al. 1980).
Known effects
- Energy intake suppression — Preclinical; mediated via MC4R in the paraventricular nucleus of the hypothalamus; the parent peptide β-MSH inhibits feeding as potently as α-MSH in rodents.
- MC4R agonism — Mechanistic; the Phe-Arg-Trp pharmacophore core is present; direct receptor binding and functional data for this specific fragment are not published.
- Sexual function modulation — Preclinical/analog evidence; MC4R agonism in limbic circuits mediates pro-erectile and pro-arousal signaling; demonstrated clinically for related MC4R agonists bremelanotide (Diamond et al. 2006; Safarinejad et al. 2008) but not for this fragment directly.
Safety signals
No safety or toxicology data for [Y9]-β-MSH[9-18] have been published. Safety information on MC4R agonism in humans derives from clinical experience with setmelanotide and bremelanotide. Setmelanotide's most common adverse effects include injection-site reactions and skin hyperpigmentation (the latter reflecting off-target MC1R activation) (Qamar et al. 2024). Earlier MC4R agonist programs were limited by cardiovascular adverse effects; setmelanotide was engineered to avoid these through receptor subtype and signaling-pathway selectivity (Qamar et al. 2024). These class-level signals do not directly predict the profile of this uncharacterized fragment.
Regulatory status
- US / EU: Not approved. [Y9]-β-MSH[9-18] is a research compound with no regulatory filing.
- WADA: Melanocortin receptor agonists fall under S2 (peptide hormones, growth factors, and related substances) on the WADA prohibited list.
Related peptides
- Setmelanotide (Imcivree) — FDA-approved (2020) cyclic MC4R agonist for monogenic and syndromic obesity caused by POMC, LEPR, or related pathway mutations; the clinical drug whose mechanism this fragment models. See setmelanotide.
- Melanotan II — Synthetic analog of α-MSH with agonist activity at MC3R and MC4R; preclinical and clinical research on this compound informed understanding of melanocortin-mediated sexual function. See Melanotan II.
- α-MSH — The primary endogenous MC4R agonist in the hypothalamic satiety circuit; shares the His-Phe-Arg-Trp core with β-MSH but differs in N- and C-terminal modifications. See α-MSH.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Do the two prolines in the middle of this peptide act as a structural brace that holds the whole molecule in the correct shape for binding its receptor?
If prolines act as scaffolds here, drug designers could use this principle to build short, rigid peptide drugs that bind metabolic receptors tightly and predictably, potentially leading to better, more stable treatments for obesity and related conditions.
Does replacing one amino acid in this appetite-controlling peptide allow it to work reliably in the acidic environment of inflamed fat tissue where normal versions might not?
Many obese patients have chronic low-grade inflammation in their fat tissue, which creates an acidic environment. If this peptide variant maintains activity under those conditions, it could be more effective than existing weight-loss drugs for patients with obesity-related inflammation, a very large and underserved population.
Does the negatively charged final amino acid of this peptide steer it specifically toward the obesity-linked receptor while avoiding the other four melanocortin receptors?
Current MC4R drugs sometimes cause side effects by activating related receptors. If this peptide's negative tail confers MC4R selectivity, it could serve as a template for more targeted obesity drugs with fewer pigmentation or immune side effects, improving treatment tolerability for the hundreds of millions of people living with obesity.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9485958814620972 | boltz-2 |
| ranking score | 0.8583270907402039 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.462 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10698,
sequence = {YFRWGSPPKD},
target = {mc4r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}