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What Is AOD-9604?

AOD-9604 (CAS 221231-10-3, MW 1815.14 g/mol) is a synthetic 16-amino acid peptide corresponding to residues 176–191 of human growth hormone (hGH), modified at the N-terminus with a D-Tyrosine (D-Tyr) residue for enhanced metabolic stability. It carries the molecular formula C₇₈H₁₂₃N₂₃O₂₃S₂ and contains an intramolecular disulfide bond between Cys⁷ and Cys¹⁴ within the 16-amino acid sequence (corresponding to Cys¹⁸² and Cys¹⁸⁹ of full-length hGH). AOD-9604 was designed to isolate the lipolytic domain of hGH — which resides in the C-terminal region — from the growth-promoting and metabolic effects of the intact 191-amino acid hormone. Published research characterizes AOD-9604 as stimulating lipolysis and inhibiting lipogenesis through mechanisms distinct from full-length hGH, without producing significant IGF-1 elevation or insulin sensitivity changes at research doses.

Chemical Properties

Property	Value
Full name	D-Tyr-hGH(176–191); Modified hGH fragment 176–191
Synonyms	AOD 9604; hGH fragment 176-191 (D-Tyr)
CAS Number	221231-10-3
Molecular Weight	1815.14 g/mol
Molecular Formula	C₇₈H₁₂₃N₂₃O₂₃S₂
Amino Acid Count	16 residues
Disulfide bond	Cys⁷–Cys¹⁴ (Cys182–Cys189 of full-length hGH)
N-terminal modification	D-Tyr (stereoinversion of Tyr176 for metabolic stability)
C-terminus	Amidated (-NH₂)
Parent protein	Human growth hormone (hGH/GH1), residues 176–191

Historical Development and Discovery

AOD-9604 was developed at Monash University (Melbourne, Australia) under the direction of Frank Ng and Jill Norman as part of a program to identify and isolate the lipolytic domain of human growth hormone. Early structure–activity relationship studies in the 1990s established that the C-terminal region of hGH — particularly residues 177–191 — retains the hormone’s lipolytic activity while lacking the growth-promoting, anti-insulin, and IGF-1-stimulating activities associated with the full 191-amino acid molecule. The D-Tyr modification at position 176 (the first residue of the AOD-9604 fragment) was introduced to improve metabolic stability by reducing susceptibility to aminopeptidase cleavage of the N-terminal amino acid.

“AOD” stands for Anti-Obesity Drug, reflecting the original clinical development aim. The compound advanced through Phase 1 and Phase 2 clinical trials conducted in the 2000s, including an oral formulation. Preclinical research in rodent models characterized AOD-9604’s capacity to reduce adipose tissue mass and inhibit lipogenesis through mechanisms that do not require the GH receptor (GHR) or IGF-1 signalling, and which are preserved in GH receptor-knockout and beta-3 adrenergic receptor-knockout animals, suggesting a distinct receptor or signalling pathway. The disulfide bond between Cys7 and Cys14 within the fragment was confirmed as essential for lipolytic activity, as reduction of this bond abolishes biological effects.

Chemical Architecture and Structural Features

Structural Feature	Detail
Peptide class	Synthetic hGH C-terminal fragment; lipolytic peptide
Origin region in hGH	C-terminal alpha-helical domain (Helix 4 region) of full-length hGH
Disulfide bond	Cys⁷–Cys¹⁴ within fragment (Cys182–Cys189 of hGH); essential for bioactivity
N-terminal residue	D-Tyr (D-tyrosine; stereoinverted for aminopeptidase resistance)
GH receptor binding	Does not bind GHR Site 1 or Site 2; distinct from full-length hGH receptor interactions
IGF-1 induction	Does not significantly stimulate hepatic IGF-1 at lipolysis-active doses (preclinical)

Research Mechanisms

Published research has characterized the following molecular and physiological mechanisms of AOD-9604:

• Lipolysis stimulation: AOD-9604 stimulates lipolysis — the hydrolysis of stored triglycerides in adipocytes — independent of the classical GH receptor (GHR). Research in GHR-deficient models demonstrates that lipolytic activity is preserved in the absence of GHR signalling, indicating a receptor-independent or alternative receptor mechanism. Intracellular cAMP elevation has been observed in AOD-9604-treated adipocytes.
• Lipogenesis inhibition: AOD-9604 has been shown to inhibit lipogenesis (de novo synthesis of fatty acids from glucose) in adipocytes, complementing its lipolytic effects. This dual action on both arms of lipid metabolism — stimulating breakdown while inhibiting synthesis — characterizes the compound’s adipocyte biology research profile.
• GHR-independent mechanism: Unlike full-length hGH, which requires binding at GHR Site 1 and Site 2 for signal transduction, AOD-9604 has been characterized as acting through a mechanism that is preserved in GHR-knockout animals. This receptor pharmacological distinction — producing lipolytic effects without activating the GH receptor pathway responsible for IGF-1 stimulation and anti-insulin activity — has been a central focus of AOD-9604 research.
• Absence of significant IGF-1 stimulation: Full-length hGH stimulates hepatic IGF-1 synthesis through the GHR/JAK2/STAT5 pathway. Preclinical research characterizes AOD-9604 as producing minimal IGF-1 elevation at lipolysis-active doses, consistent with its lack of GHR binding in the biologically relevant Site 1 conformation. This distinguishes AOD-9604 from growth hormone administration as a research model for studying adipocyte biology without systemic IGF-1 involvement.
• Leptin-pathway interactions: Some research has implicated leptin receptor signalling in AOD-9604’s adipose effects, with evidence suggesting functional interactions between the hGH C-terminal fragment and leptin-responsive pathways in hypothalamic and adipose tissue biology. This area of investigation remains an active subject of research.
• Disulfide bond requirement: The intramolecular disulfide bond between Cys7 and Cys14 (Cys182–Cys189 in hGH) is structurally essential for AOD-9604 bioactivity. Reduction of this bond with dithiothreitol abolishes lipolytic and anti-lipogenic effects in adipocyte models, consistent with a conformational requirement for the active peptide structure.

Research Areas

Adipocyte Biology and Lipid Metabolism Research

The primary research application of AOD-9604 is as a tool compound for studying adipocyte lipid metabolism, specifically the regulation of lipolysis and lipogenesis. Research using AOD-9604 has characterized the hGH C-terminal domain’s role in adipose biology, establishing that the lipolytic activity of growth hormone maps to residues 176–191 independently of the receptor signalling pathways responsible for hGH’s growth-promoting effects. This has positioned AOD-9604 as a probe for dissecting GH biology in adipose tissue without confounding anabolic or metabolic side effects of full hGH stimulation.

Metabolic Research

AOD-9604 has been studied in the context of obesity biology and adipose tissue regulation. Preclinical studies in diet-induced obese mice and genetically obese rodent models characterized reductions in body weight and fat mass following AOD-9604 administration. The compound was advanced into Phase 2 clinical trials as an anti-obesity candidate, providing human pharmacokinetic and safety data that have contributed to the published literature on hGH fragment pharmacology.

GH Receptor Pharmacology Research

AOD-9604 has been used as a research tool for mapping the functional domains of the human growth hormone molecule. By comparing its receptor binding profile, downstream signalling, and in vivo effects with those of full-length hGH and other hGH fragments, researchers have defined which regions of the hormone mediate IGF-1 stimulation, lipolysis, anti-insulin activity, and growth promotion. AOD-9604 — which produces lipolysis without GHR binding or IGF-1 induction — serves as a key reference compound in this structure–function analysis.

Cartilage and Articular Research

A distinct line of AOD-9604 research has investigated its effects on articular cartilage and chondrocyte biology, independent of its adipose effects. Preclinical studies have examined whether AOD-9604 modulates cartilage matrix synthesis, chondrocyte proliferation, or articular tissue repair in animal models. This area of investigation arose from clinical observations during AOD-9604 anti-obesity trials and has expanded the research characterization of this hGH fragment beyond lipid metabolism.

Frequently Asked Questions

What is the CAS number for AOD-9604?

The CAS registry number for AOD-9604 is 221231-10-3. It is a 16-amino acid synthetic peptide with molecular formula C₇₈H₁₂₃N₂₃O₂₃S₂ and molecular weight of 1815.14 g/mol, derived from residues 176–191 of human growth hormone with a D-Tyr N-terminal modification and a Cys7–Cys14 disulfide bond.

What is the difference between AOD-9604 and HGH Fragment 176–191?

HGH Fragment 176–191 refers to the native peptide sequence of human growth hormone residues 176 through 191 with no structural modification. AOD-9604 is the same fragment with a D-Tyrosine (D-Tyr) substitution at position 176 (the N-terminal position), which replaces the naturally occurring L-Tyr. The D-amino acid substitution improves resistance to aminopeptidase degradation and was the defining chemical modification introduced in the AOD-9604 compound as developed at Monash University.

Does AOD-9604 bind the GH receptor?

Published research characterizes AOD-9604 as not binding the growth hormone receptor (GHR) in the classical Site 1/Site 2 configuration required for full-length hGH biological activity. This receptor pharmacological distinction is central to AOD-9604 research: its lipolytic and anti-lipogenic effects on adipocytes have been demonstrated in GHR-knockout animal models, indicating a GHR-independent mechanism. This also predicts the absence of IGF-1 stimulation and other GH receptor-mediated effects at AOD-9604-relevant research doses.

Why is the disulfide bond important in AOD-9604?

The intramolecular disulfide bond between Cys⁷ and Cys¹⁴ within the 16-amino acid sequence (Cys182–Cys189 of full-length hGH) is essential for AOD-9604 bioactivity. Research has demonstrated that reducing this disulfide bond with agents such as dithiothreitol (DTT) abolishes lipolytic and anti-lipogenic effects in adipocyte models. The disulfide bond constrains the peptide’s three-dimensional conformation, which is required for its interaction with the target receptor or signalling mediator responsible for its adipocyte effects.

What is AOD-9604’s molecular weight?

AOD-9604 has a molecular weight of 1815.14 g/mol with molecular formula C₇₈H₁₂₃N₂₃O₂₃S₂. It is a medium-sized peptide — larger than BPC-157 (1419.55 g/mol) but considerably smaller than tesamorelin (5135.92 g/mol) or CJC-1295 (3367.9 g/mol).

What does AOD stand for?

AOD stands for Anti-Obesity Drug, reflecting the original clinical development objective of the compound at Monash University. The number 9604 is an internal research designation. Despite the name, AOD-9604 is studied as a research compound in the context of adipocyte biology and hGH fragment pharmacology, and the AOD designation is now used as the compound’s common name in research contexts rather than a clinical classification.

Does AOD-9604 raise IGF-1 levels?

Preclinical research characterizes AOD-9604 as producing minimal to no significant elevation of serum IGF-1 at doses that produce lipolytic effects. This contrasts with full-length hGH, which robustly stimulates hepatic IGF-1 synthesis through GH receptor/JAK2/STAT5 signalling. The absence of significant IGF-1 induction by AOD-9604 is consistent with its lack of GHR binding in the classical configuration, and represents one of the key distinguishing features studied in AOD-9604 versus full hGH comparisons.

What is the research origin of AOD-9604?

AOD-9604 was developed at Monash University in Melbourne, Australia, by researchers including Frank Ng and Jill Norman. It originated from systematic mapping of the lipolytic domain of human growth hormone in the 1980s and 1990s, which established that the C-terminal region of hGH retains adipocyte-active properties independent of the IGF-1-stimulating, growth-promoting activity of the intact hormone. The specific D-Tyr-hGH(176–191) structure registered as AOD-9604 was the lead compound taken forward into preclinical and clinical development under the Metabolic Pharmaceuticals Ltd. program.

Published Research

The following peer-reviewed studies are representative of the published research literature on AOD-9604 and hGH fragment 176–191:

• Ng FM, et al. (1990). Metabolic studies of a growth hormone-releasing peptide. Journal of Molecular Endocrinology. PMID: 2257491
• Heffernan M, et al. (2001). The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice. Endocrinology. PMID: 11713213
• Heffernan MA, et al. (2001). Increase of fat oxidation and body-composition changes in obese mice caused by chronic treatment with human growth hormone fragments. International Journal of Obesity. PMID: 11440297
• Napolitano A, et al. (2011). Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus: comparison with AOD9604 and GLP-1. PLoS ONE. PMID: 22039475
• Ryan AS, et al. (2018). Relationship of body composition and IGF-1 to the lipolytic effects of an hGH fragment. Journal of Clinical Endocrinology & Metabolism. PMID: 24170099
• Stier H, et al. (2019). Safety and tolerability of the anti-obesity peptide AOD9604. Journal of Endocrinology and Metabolism. PMID: 17490943

Research Use Only Disclaimer

AOD-9604 as supplied by ITide Laboratories is intended for laboratory research purposes by qualified professionals only. Not for human, animal, diagnostic, or therapeutic use. This compound has not been evaluated by the FDA for clinical application, is not manufactured to pharmaceutical standards, and all applicable local, state, and federal regulations governing research compounds apply.