Cortisol-pathway research fragment (ACTH 7: 39)
A lab-made piece of the stress hormone ACTH that weakly switches on the adrenal gland's cortisol receptor, used in research to study how cortisol release is triggered; not an approved drug.
- Class
- Pituitary hormone; melanocortin receptor agonist
- Status
- FDA-approved prescription drug (cosyntropin / Acthar Gel); prescription-only across all major markets
- Best-supported effect
- Adrenal insufficiency diagnosis via cosyntropin stimulation test (human, approved); infantile spasms treatment with strong RCT support (human, approved)
- Main caveat
- Evidence is confined to narrow specialist indications under clinician supervision; not established for wellness, performance, or self-administration use
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
ACTH(7–39) is a 33-residue fragment of adrenocorticotropic hormone (ACTH) that spans positions 7 through 39 of the full 39-amino-acid pituitary peptide. It is not a natural product of proopiomelanocortin (POMC) processing in the body — tissue endoproteases that cleave POMC generate full-length ACTH(1–39) and shorter fragments such as α-MSH(1–13), but not this particular N-terminally truncated form (Harno and colleagues, Physiological Reviews 2018). ACTH(7–39) exists as a pharmacological research tool, constructed to probe which regions of ACTH are required for binding and activating the melanocortin-2 receptor (MC2R) — the adrenal receptor responsible for driving cortisol synthesis. It has no approved clinical use.
The stored sequence FRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF is the 33-residue backbone with no further modifications; it represents the straight-chain peptide starting at the phenylalanine that is position 7 in the full ACTH sequence.
History
ACTH(7–39) emerged from structure-activity relationship work on the melanocortin receptor system aimed at understanding which amino acid positions are essential for MC2R binding and activation. The receptor pharmacology of ACTH was analyzed in detail once MC2R was cloned and expressed, enabling researchers to test truncated and mutated fragments systematically. Fridmanis and colleagues (Frontiers in Endocrinology 2017) reviewed the molecular basis of MC2R specificity in detail, noting that the HFRWG N-terminal segment and the KKRRP mid-sequence motif each contribute differently to receptor engagement. The design of ACTH(7–39) — which retains KKRRP but removes the first six residues including the histidine critical to the HFRWG pharmacophore — was part of that systematic dissection. The broader context of designing selective melanocortin receptor antagonists was reviewed by Hruby and colleagues (Expert Opinion on Drug Discovery 2011).
What it does
Because ACTH(7–39) lacks the first six residues of ACTH — including the histidine at position 6 that is a key part of the HFRWG activating pharmacophore — it cannot fully drive MC2R signaling the way full-length ACTH does. However, it retains the KKRRP sequence (positions 15–19 of full ACTH) that contributes to MC2R selectivity: MC2R is the only melanocortin receptor among the five-member family that requires this mid-sequence motif for efficient binding, which is part of what makes it distinct from MC1R, MC3R, MC4R, and MC5R (Fridmanis and colleagues, Frontiers in Endocrinology 2017). The result is a peptide that competes with native ACTH at MC2R — binding the receptor but producing reduced or no activation — making it useful in laboratory settings to characterize MC2R pharmacology and test the contribution of the N-terminal region to adrenal signaling.
Evidence
- Human: No human studies. ACTH(7–39) is a pharmacological research tool with no documented clinical or human experimental use.
- Animal: Not individually extracted from the available literature. Studies on truncated ACTH fragments in adrenocortical preparations have been conducted in isolated tissue and cell models; individual animal studies with this specific fragment were not extracted from the available dossier sources.
- In vitro: ACTH(7–39) is characterized primarily through receptor-binding and cell-based assays demonstrating reduced MC2R activation relative to full-length ACTH, consistent with its classification as a partial agonist/competitive antagonist. Individual assay values (IC50, Ki, EC50) were not extracted from the available dossier sources.
Known effects
- MC2R partial agonism / competitive antagonism — Pharmacological (in vitro / receptor binding); reduces MC2R signaling relative to full-length ACTH; no in vivo human data
- No adrenal cortisol drive — Not established; the truncation eliminates the HFRWG N-terminal pharmacophore required for full MC2R activation; no cortisol-stimulating clinical use
- MC2R selectivity probe — Research tool; the retained KKRRP motif preserves selectivity for MC2R over other melanocortin receptors, making this fragment useful for dissecting receptor specificity
Regulatory status
- US (FDA): Not approved. Research tool only; no IND, NDA, or approved indication.
- EU / international: Not approved in any jurisdiction.
- WADA: Not listed as a prohibited compound in available sources (distinct from full-length corticotropin / cosyntropin, which are prohibited under WADA S9).
- Compounding: Not part of the compounded-peptide market.
Mechanism
ACTH(7–39) targets MC2R, the Gs-coupled melanocortin receptor expressed predominantly on adrenocortical cells of the zona fasciculata and responsible for cortisol synthesis. Full-length ACTH(1–39) engages MC2R through two partially separable regions: the N-terminal HFRWG segment (residues 6–10 of the full sequence), which is important for receptor activation, and the KKRRP motif (residues 15–19), which confers the selectivity of MC2R for ACTH-class ligands over the shorter α-MSH and other melanocortins (Fridmanis and colleagues, Frontiers in Endocrinology 2017). ACTH(7–39) starts at position 7 (F), removing the S-Y-S-M-E-H leading residues. Loss of His6 disrupts the HFRWG activating element, reducing or eliminating the cAMP/PKA/StAR cascade that drives steroidogenesis when full-length ACTH binds. The retained KKRRP motif means the fragment can still occupy MC2R — it binds but does not fully activate, producing partial agonism or competitive antagonism depending on assay conditions and relative concentrations.
The melanocortin pathway more broadly — linking POMC processing in the pituitary to adrenal steroidogenesis via MC2R — was reviewed by Yeo and colleagues (Molecular Metabolism 2021) and Ericson and colleagues (Biochimica et Biophysica Acta 2017). ACTH(7–39) is distinguished from cosyntropin (ACTH 1–24), which retains the full HFRWG pharmacophore and fully activates MC2R; cosyntropin is the diagnostic fragment used clinically to test adrenal reserve.
Open questions
- Quantitative binding characterization: Ki, IC50, and EC50 values for ACTH(7–39) at MC2R are not consolidated in the available literature; rigorous head-to-head comparisons with full-length ACTH and cosyntropin in standardized assay systems would sharpen its pharmacological profile.
- Partial agonism versus full antagonism: Whether ACTH(7–39) behaves as a partial agonist (low intrinsic efficacy) or a competitive antagonist (near-zero intrinsic efficacy) may depend on expression system and receptor density; this distinction matters for its utility as a tool compound.
- Selectivity across melanocortin receptors: Systematic binding profiles across MC1R, MC3R, MC4R, and MC5R — where KKRRP is less critical for binding — have not been individually extracted from the dossier; off-target activity at other melanocortin receptors is not characterized in available sources.
- In vivo utility: No in vivo studies using ACTH(7–39) as a competitive probe in adrenocortical physiology have been identified in the available literature.
Related peptides
ACTH(7–39) is derived from the same POMC-derived ACTH(1–39) parent sequence and shares its C-terminal half with full-length ACTH. For the parent hormone and its approved clinical forms, see the full ACTH card. For the rational design context of melanocortin receptor antagonists more broadly, the literature reviewed by Hruby and colleagues (Expert Opinion on Drug Discovery 2011) covers the design principles that motivated truncation studies like this one.
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.
Does this shortened hormone fragment sit on the receptor without fully turning it on?
If true, it could become a safer way to fine-tune adrenal hormone signaling in diseases where cortisol is too high or too low, without the side effects of full stimulation.
Can the central basic patch of ACTH bind the adrenal receptor even when the N-terminus is cut off?
If true, researchers could design much shorter ACTH-like drugs that are easier to manufacture and deliver, which would help patients with adrenal insufficiency who currently need large protein injections.
Could this shortened fragment work on different melanocortin receptors in the brain, skin, or immune system?
If true, it could lead to new treatments for obesity, skin disorders, or inflammatory diseases by hitting the right receptor subtype without affecting the adrenal gland.
Could a weaker version of this hormone help patients whose adrenal glands work only a little?
If true, people with congenital adrenal problems could get steadier hormone levels with fewer dangerous spikes, reducing the need for constant dose adjustment.
Does the back end of this peptide keep the front end in the right shape for the receptor?
If true, drug designers would know they cannot simply chop off the tail to make a smaller medicine, and would instead need to replace it with a rigid synthetic scaffold.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.5916587710380554 | boltz-2 |
| ranking score | 0.735288143157959 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10780,
sequence = {FRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF},
target = {mc2r},
author = {peptidemodel},
year = {2026},
status = {computed}
}