AOD-9604 vs hGH Fragment 176-191: What One Tyrosine Changes

Line the two sequences up and you can miss the difference entirely. One starts with phenylalanine. The other starts with tyrosine. The remaining fifteen residues are identical. Both are supplied strictly for research use only, both run sixteen amino acids, and both come from the tail end of human growth hormone — and yet they carry different CAS numbers, different molecular formulas, and research records that barely overlap. So if you're looking at listings for AOD-9604 and hGH fragment 176-191 and wondering whether the two names describe the same material, the answer is no. The reason sits entirely in position one of the chain. What follows puts the structures side by side, works out what one hydroxyl group actually changes, separates what the studies measured from which molecule they measured it on, and closes with where the regulatory picture stands.

Where Residues 176-191 Sit in the Growth Hormone Molecule

Short answer: 176-191 is the last sixteen residues of a 191-residue protein — the tail, not the business end most people picture when they think about growth hormone.

Human growth hormone is a single polypeptide chain, 191 amino acids long, folded into a compact four-helix bundle. The regions that engage the growth hormone receptor are scattered across that fold, which is why the intact hormone sets off such a broad set of signaling consequences. Residues 176 through 191 sit out in the C-terminal region, near the end of the chain.

The question that produced both peptides was structure-function: does a short, defined stretch of the hormone carry a specific metabolic activity on its own? A sixteen-residue segment is attractive for that work in a way a 191-residue protein never will be. You can build it cleanly by solid-phase synthesis, characterize it with routine methods, and test it without dragging along the receptor engagement the folded hormone brings with it.

The Two Structures, Side by Side

Short answer: identical backbones, identical disulfide loop, one different residue at the front, and about sixteen daltons of mass between them.

Sequences and the single point of difference

The unmodified fragment is H-Phe-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe-OH, with phenylalanine at the N-terminus — the native residue 176 of human growth hormone. AOD-9604 is H-Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe-OH, or YLRIVQCRSVEGSCGF in one-letter notation. Read from position two onward and you're reading the same peptide twice. Read position one and you aren't.

Formulas, masses, and identifiers

The arithmetic is tidy. The unmodified 176-191 fragment is C₇₈H₁₂₃N₂₃O₂₂S₂, molar mass near 1799.10 g/mol, CAS 66004-57-7. AOD-9604 is C₇₈H₁₂₃N₂₃O₂₃S₂ at roughly 1815.10 g/mol, CAS 221231-10-3. Same carbon, hydrogen, nitrogen, and sulfur counts. One extra oxygen atom. About sixteen daltons of extra mass. That lone oxygen is the phenol hydroxyl separating tyrosine from phenylalanine, and it is the whole structural story.

The part that doesn't change

Both peptides carry two cysteine residues inside the sixteen-mer, and in both cases those cysteines form an intramolecular disulfide bridge. The FDA's characterization of AOD-9604 puts the bond between cysteines at positions 7 and 14. That bridge pulls the middle of the chain into a closed loop and narrows the conformations the peptide can adopt in solution — the same principle at work in disulfide-constrained peptide rings elsewhere in peptide chemistry. Worth stating plainly: the constrained core is shared. Only the residue at the entrance differs.

Why Tyrosine Instead of Phenylalanine?

Short answer: tyrosine is phenylalanine with a hydroxyl group bolted onto the aromatic ring, and that hydroxyl buys the chemists several things the plain residue can't provide.

What the swap changes chemically

Phenylalanine carries a plain benzyl side chain — aromatic, bulky, almost entirely nonpolar. Tyrosine is that same side chain with a hydroxyl added at the para position of the ring. One substitution, three consequences. The N-terminal residue picks up a hydrogen-bond donor it didn't have before. Local polarity at that end of the peptide shifts measurably. And the residue gains a distinct ultraviolet absorbance profile, with the phenol chromophore absorbing far more strongly near 275-280 nm than phenylalanine manages anywhere in that region.

Why this is a design choice, not an accident

The formal nomenclature makes the intent explicit. The National Library of Medicine's controlled vocabulary defines the compound as "an N-tyrosyl analog of the lipolytic fragment of human growth hormone." The modification isn't a footnote to the name. It's what the name encodes.

It also explains a piece of notation that trips people up when they read two sources side by side. Some references describe AOD-9604 as hGH residues 176-191 with tyrosine in place of the phenylalanine at the N-terminal end. Others, the FDA briefing material among them, describe it as the hGH 177-191 segment with an additional tyrosine attached at the N-terminus. Both land on the same sixteen-residue molecule — the first frames it as a substitution, the second as a truncation plus an addition. Neither is wrong.

Modifying a terminal residue while leaving the body of a peptide alone is a recurring move in this field, and it's the same logic that governs the N-terminal chemistry of GHRH analogs. Chain ends are where chemists intervene most readily, because the backbone downstream stays intact and the structural consequences stay local.

The Tyrosine as an Analytical Handle

Short answer: a tyrosine gives you somewhere to attach a radiolabel and a clean signal to measure, which makes the peptide far easier to follow through an experiment.

Detection and labeling

The phenol ring of tyrosine is the conventional site for radioiodination in peptide chemistry. Iodine substitutes readily onto the activated aromatic ring, which turns the peptide into a traceable species for binding assays and displacement studies. A peptide whose only aromatic residues are phenylalanines offers no such convenience. The tyrosine absorbance maximum is useful for the same reason — it gives a straightforward spectrophotometric readout for concentration and purity work, where the unmodified fragment stays comparatively quiet in the near-UV.

Modeling and docking

The tyrosine-bearing sequence is also the working molecule in contemporary computational work. A 2022 in-vitro and in-silico study on this peptide family built its model from YLRIVQCRSVEGSCGF using PEP-FOLD3.5, then carried it into molecular docking against several protein targets. There's a general point hiding in that choice: an aromatic residue bearing a polar substituent at a chain terminus tends to participate in exactly the contacts docking scores reward. Its presence isn't computationally neutral either.

What the Research Measured — and on Which Molecule

Short answer: the animal and human study record attaches to AOD-9604. The unmodified fragment hasn't been through the same work, and much of what gets said about it is borrowed.

The rodent studies

In obese-mouse models, chronic treatment with human growth hormone or the modified C-terminal fragment was associated with increased fat oxidation, stimulated lipolysis, and a lower rate of body-mass gain. What made the fragment interesting wasn't an effect, though — it was a dissociation. The fragment didn't interact with the growth hormone receptor, and unlike the full-length hormone it came without hyperglycaemia or suppressed insulin secretion in those animals. We'd call that the central structure-function argument for working with a short C-terminal analog at all: the metabolic activity observed appears to travel through pathways distinct from classical receptor-mediated growth hormone signaling.

The beta-3 adrenergic receptor question

A companion study went after the beta-3 adrenergic receptor specifically, the principal lipolytic receptor on fat cells. Lipolytic sensitivity tracked with increased beta-3 adrenergic receptor RNA expression, and knockout animals lacking the receptor were unresponsive. The authors' own conclusion is more careful than that correlation alone would suggest: the lipolytic actions of both growth hormone and the fragment are not mediated directly through the beta-3 adrenergic receptor, even though both compounds raise its expression — and that raised expression may in turn feed the sensitivity observed. The gap between "acts through receptor X" and "raises expression of receptor X" is a real one, and secondary summaries flatten it constantly.

Which molecule the data belongs to

Early human research on AOD-9604 reported that it retained the lipolytic characteristics associated with growth hormone without stimulating IGF-1 production. That is a statement about AOD-9604. On the other half of the picture, reference sources are blunt: the unmodified hGH fragment 176-191 has not been studied in humans, and lipolytic descriptions of it rest on extrapolation from AOD-9604 data rather than any record of its own. Neither peptide is a pharmaceutical product. Research-grade material of either is a laboratory chemical with no approved equivalent.

Why the Two Names Get Swapped

Short answer: one research narrative attached to two compound names, and secondary writing that rarely bothers to pull them apart.

The mechanism is straightforward. The published data came from AOD-9604, so the vocabulary used to describe this peptide family — lipolytic fragment, C-terminal fragment, growth hormone fragment — originated in work on the tyrosine-bearing analog. The unmodified fragment inherited the vocabulary without inheriting the evidence, and after enough iterations of secondary writing the two labels start working as synonyms. It's the same failure mode we've described for two unrelated peptides sharing one name, approached from the opposite direction: there, one name covered two molecules; here, two names collapsed onto one body of research.

The practical response is to stop treating the product label as an identity claim. The sequence and the CAS number are the unambiguous identifiers — 66004-57-7 and 221231-10-3 describe different materials no matter how a listing is worded, and that's exactly the question a certificate of analysis is supposed to settle. Note too that the FDA's review flagged peptide-related impurity profiles and active-ingredient characterization as specific concerns for this compound. When the reviewing agency calls characterization complex, identity documentation becomes the first question to ask, not the last.

Where This Leaves the Regulatory Picture

Short answer: AOD-9604 has been reviewed and declined. The unmodified fragment hasn't been reviewed at all — a different thing from being cleared.

Commercial development of AOD-9604 stopped in 2007. A twelve-week human study had shown a modest separation from placebo; a twenty-four-week study that followed didn't reproduce it, and the program ended without approval. The compound remains on anti-doping prohibited lists and is screened for in competition testing.

The current United States position is more recent. At the Pharmacy Compounding Advisory Committee meeting held on December 4, 2024, the FDA proposed that neither AOD-9604 free base nor AOD-9604 acetate be added to the 503A bulk drug substances list. The briefing material cited a failure to demonstrate benefit versus placebo for the nominated use, significant immunogenicity risk tied to certain delivery routes, and the characterization complexities noted above. The unmodified 176-191 fragment has no comparable regulatory file at all — an absence of review, not a clean bill of health.

Frequently Asked Questions

Are AOD-9604 and hGH fragment 176-191 the same peptide?

No. They differ by a single residue at the N-terminus. The unmodified fragment begins with phenylalanine, the native residue 176 of human growth hormone; AOD-9604 carries a tyrosine in that position. Everything after that first residue is identical, disulfide bridge included — but the two compounds carry different CAS numbers, different molecular formulas, and very different research histories.

How much does one tyrosine actually change the molecule?

On paper, one oxygen atom and roughly sixteen daltons. The unmodified fragment is C78H123N23O22S2 at about 1799.10 g/mol; AOD-9604 is C78H123N23O23S2 at about 1815.10 g/mol. Tyrosine is phenylalanine with a hydroxyl added to the aromatic ring, so the swap changes the N-terminal residue's polarity, its capacity to donate a hydrogen bond, and its ultraviolet absorbance — without touching the backbone or the cysteine loop.

Why do suppliers and articles often treat the two names as interchangeable?

Because the research literature is lopsided. The published animal and human studies were run on AOD-9604, so descriptive language about lipolytic activity originated there. Reference sources note that the unmodified 176-191 fragment has been presented as a lipolytic fragment largely by extrapolation from AOD-9604 data, and that it has not itself been studied in humans.

Does AOD-9604 bind the growth hormone receptor?

Published rodent work indicates it does not. In the obese-mouse studies, the modified C-terminal fragment produced effects on fat oxidation and lipolytic activity without interacting with the growth hormone receptor, and without the hyperglycaemia or suppressed insulin secretion seen with the full-length hormone.

What is the current regulatory status of AOD-9604 in the United States?

It is not an approved product. Development was halted in 2007 after a twenty-four-week study failed to reproduce the modest separation from placebo seen in a shorter one. At the December 4, 2024 Pharmacy Compounding Advisory Committee meeting, the FDA proposed that neither AOD-9604 free base nor AOD-9604 acetate be added to the 503A bulk drug substances list, citing absent benefit versus placebo, immunogenicity risk for certain delivery routes, and difficulty characterizing peptide-related impurities. It also remains on anti-doping prohibited lists.

One Hydroxyl, Two Compounds

A single hydroxyl group at one end of a sixteen-residue chain is the entire structural difference between AOD-9604 and hGH fragment 176-191 — and it's enough to yield two compounds with separate registry numbers, separate analytical behavior, and research records that don't transfer between them. What the tyrosine bought the chemists was tractability: a site for radioiodination, a usable ultraviolet signal, and a molecule they could follow through binding experiments. What it didn't buy was a shared evidence base for its unmodified sibling. The sequence and the CAS number settle a question the product name leaves open. If structural characterization is the thread to follow next, our write-up on solving peptide structures in solution picks it up there.

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