AOD-9604 – Norleucine-Modified hGH Fragment 176–191

Chemical Identity

Chemical Name: AOD-9604 Acetate
Molecular Formula: C₇₈H₁₂₃N₂₃O₂₃S₂
Molecular Weight: ~1815.1 Da
CAS Number: 221231-10-3
Sequence (Linear): Nle-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe
Structure Type: Synthetic 16-amino acid C-terminal fragment of human growth hormone with a Norleucine substitution at position 1

Pharmacological Classification

AOD-9604 is a **modified fragment** of human growth hormone (hGH 176–191) developed by substituting Tyrosine (Tyr) at position 1 with Norleucine (Nle). This change enhances peptide stability while preserving its lipolytic activity and eliminating mitogenic and IGF-1–mediated effects. It does not activate the growth hormone receptor.

Mechanism of Action

• Stimulates Lipolysis: Enhances activity of hormone-sensitive lipase (HSL) and mobilizes adipocyte-stored triglycerides.
• Inhibits Lipogenesis: Suppresses transcription of fatty acid synthase and acetyl-CoA carboxylase enzymes.
• Receptor-Independent Action: Functions independently of GH receptor activation; does not increase IGF-1 levels.

β-Arrestin Recruitment

AOD-9604 does not bind to G protein-coupled receptors (GPCRs) and exhibits no β-arrestin recruitment. Its effects are not mediated by classical receptor-ligand signaling but rather via indirect activation of metabolic regulatory pathways such as AMPK and PPARs.

Molecular Engineering

The Norleucine substitution at position 1 improves proteolytic resistance and enhances peptide half-life without affecting receptor specificity. AOD-9604 retains the full bioactivity of the native 176–191 fragment with superior pharmaceutical properties.

Pharmacokinetics (Non-Dosing)

• Absorption: Rapid following subcutaneous administration
• Half-Life: Short (approx. 1–2 hours), though downstream metabolic effects are prolonged
• Elimination: Primarily via renal proteolytic degradation

Biological Effects

AOD-9604 reduces visceral and subcutaneous fat mass, increases fatty acid oxidation, and improves lipid metabolism in preclinical models. It does not stimulate muscle growth, glucose uptake, or IGF-1 synthesis — differentiating it from full-length hGH.

Preclinical Evidence

In high-fat diet–induced obesity models (rodent, canine, and primate), AOD-9604 reduced adipose tissue accumulation and improved serum lipid profiles. Studies demonstrate a favorable safety profile, with no evidence of carcinogenic or mitogenic activity.

Stability and Storage

• Form: Lyophilized acetate salt
• Solubility: Water, pH 4–5 buffers, DMSO (for research use)
• Storage: –20°C; light- and moisture-protected
• Reconstitution pH: 4.5–5.5 preferred

Comparative Mechanistic Summary

Parameter	hGH (176–191)	AOD-9604
Position 1 Residue	Tyrosine (Tyr)	Norleucine (Nle)
GH Receptor Binding	No	No
IGF-1 Induction	No	No
Lipolytic Activity	Yes	Yes
Stability	Lower	Enhanced (due to Nle)

References

1. Heffernan M, Ng FM. Obesity. 2001;9(3):341–345.
2. Ng FM, et al. Obes Res. 2000;8(6):431–435.
3. Le Roith D, et al. Endocr Rev. 2001;22(1):53–74.
4. Waters MJ, et al. J Endocrinol. 2016;229(1):R1–R19.
5. Metabolic Pharmaceuticals Ltd. AOD-9604 Dossier. Clinical Trials Registry (AUS, 2002–2005).