Description
Summary Abstract
MK-677 (Ibutamoren; Ibutamoren mesylate; CAS 159752-10-0; L-163,191) is an orally bioavailable, non-peptide growth hormone secretagogue (GHS) that acts as a potent and selective agonist at the growth hormone secretagogue receptor type 1a (GHSR-1a), also designated the ghrelin receptor. By mimicking the action of endogenous ghrelin, MK-677 stimulates pulsatile growth hormone (GH) release from pituitary somatotrophs and elevates circulating insulin-like growth factor-1 (IGF-1) in a dose-dependent manner. Clinical trials lasting up to 12 months have demonstrated sustained increases in GH pulse amplitude, IGF-1 normalization, and improvements in lean body mass without serious adverse effects, distinguishing MK-677 from exogenous GH replacement by preserving the physiological pulsatility of secretion.
Clinical Indications
Research has evaluated MK-677 across GH-axis–related contexts:
- Age-related GH decline: A 12-month randomized controlled trial in healthy older adults demonstrated that 25 mg daily restored 24-hour mean GH and IGF-1 to levels observed in young adults, with increased fat-free mass and attenuated visceral fat.
- GH deficiency and lean body mass: MK-677 increases fat-free mass and muscle cross-sectional area in GH-deficient and catabolic models, making it a research tool for sarcopenia and catabolic illness pathways.
- Bone metabolism: IGF-1 elevation following MK-677 treatment is associated with increased bone turnover markers; investigated in hip fracture and osteoporosis models for its potential to stimulate bone formation.
Contraindications
- Insulin resistance and glucose intolerance: MK-677 has been documented to transiently increase fasting blood glucose and insulin resistance; caution is indicated in diabetic or insulin-resistant experimental models.
- Fluid retention: GH-axis activation via MK-677 can increase sodium and water retention, producing mild peripheral edema — a documented dose-dependent effect in clinical trials.
- Active or GH-responsive neoplasm models: As a GH/IGF-1 pathway activator, MK-677 is not appropriate for models where GH-axis stimulation could be a confounding growth factor.
Mechanism of Action (MOA)
MK-677 activates the GH axis through selective ghrelin receptor agonism, producing downstream metabolic and anabolic effects:
GHSR-1a Agonism
MK-677 binds with high affinity and selectivity to the growth hormone secretagogue receptor type 1a (GHSR-1a), a G-protein–coupled receptor expressed on pituitary somatotrophs, hypothalamic neurons, and peripheral tissues. Receptor activation triggers a Gq/11-mediated calcium signaling cascade that stimulates GH vesicle exocytosis.
Pulsatile GH Release and IGF-1 Induction
Unlike continuous GH infusion, MK-677 enhances pulsatile GH secretion, preserving physiologically relevant GH oscillations. Elevated GH stimulates hepatic production of IGF-1, which mediates downstream anabolic effects on muscle and bone through insulin receptor substrate (IRS) pathways.
Hypothalamic GHRH Potentiation
MK-677 acts synergistically with endogenous GHRH (growth hormone–releasing hormone) to amplify GH pulse amplitude. It also suppresses somatostatin tone in the hypothalamus, removing a key brake on GH secretion without suppressing the feedback axis.
Orexigenic and Metabolic Effects
As a ghrelin mimetic, MK-677 engages appetite-regulating circuits in the hypothalamus (NPY/AgRP neurons), increasing caloric intake — an important confound variable in body composition studies. It also promotes REM sleep duration and has been studied in models of sleep disturbance and nocturnal GH secretion.
Key Features & Specifications
MK-677 is the only orally active, non-peptide GHSR-1a agonist with extensive published clinical pharmacology data:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| IUPAC Name | 2-amino-2-methyl-N-[(2R)-1-(1-methylsulfonylspiro[2H-indole-3,4′-piperidine]-1′-yl)-1-oxo-3-(phenylmethoxy)propan-2-yl]propanamide; methanesulfonic acid |
| CAS Number | 159752-10-0 (mesylate salt) |
| Molecular Formula | C28H40N4O8S2 (mesylate) |
| Molecular Weight | 624.8 g/mol (mesylate) |
| PubChem CID | 6450830 |
| Synonyms | Ibutamoren, Ibutamoren mesylate, MK-0677, L-163,191, Nutrobal, Crescendo |
| Form / Variation | 25 MG Capsules — C-025 ($84.00) / 30 MG/mL Liquid 30 mL — L-006 ($68.00) |
Storage, Safety, and Handling
Storage Protocol
Capsules: store at controlled room temperature (15–25 °C), away from moisture and direct light. Liquid formulation: store at 2–8 °C; bring to room temperature before use. Liquid should be used within the labeled shelf-life period once opened; do not freeze the liquid formulation.
Handling & Compliance
Standard laboratory PPE is recommended. MK-677 is not a controlled substance under US federal scheduling; however, it is prohibited in competitive sport by WADA under S2 (Peptide Hormones, Growth Factors) and relevant regulatory frameworks should be reviewed for the specific research context. Researchers should ensure institutional compliance with GH-axis modulator research protocols.