GHRP-2 (dalanamorelin) and GHRP-6 (hexarelin) are both synthetic growth hormone secretagogue peptides that activate the ghrelin receptor (GHS-R1a), yet they differ significantly in receptor selectivity, off-target effects, and pharmacological profiles. GHRP-2 demonstrates greater selectivity for GHS-R1a with fewer off-target effects, while GHRP-6 exhibits broader receptor activity that contributes to additional physiological effects.
- Sequence: D-Ala-D-2-Nal-Ala-Trp-D-Phe-Lys-NH₂
- Molecular weight: ~823 Da
- Classification: Synthetic hexapeptide, ghrelin receptor agonist
- Key feature: D-amino acid substitution at position 1 for metabolic stability
- Sequence: His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂
- Molecular weight: ~873 Da
- Classification: Synthetic hexapeptide, ghrelin receptor agonist
- Key feature: D-amino acid substitution at position 2 for metabolic stability
| Parameter | GHRP-2 | GHRP-6 |
|---|
| IC50 at GHS-R1a | ~2 nM | ~10 nM |
| Efficacy | Full agonist | Full agonist |
| Selectivity vs other receptors | High | Moderate |
| Endogenous ligand mimicry | Ghrelin | Ghrelin |
GHRP-2 demonstrates approximately 5-fold greater potency at GHS-R1a compared to GHRP-6, translating to lower effective doses for equivalent GH stimulation.
| Receptor | GHRP-2 | GHRP-6 | Clinical Impact |
|---|
| GHS-R1a (ghrelin) | ++++ | +++ | Primary (GH release) |
| GHS-R1b (inactive splice) | ± | + | Unknown |
| CD36 (fatty acid translocase) | − | ++ | Lipid metabolism |
| MC2R (ACTH) | ± | ++ | Cortisol elevation |
| MC3R | − | + | Energy homeostasis |
| MC4R | − | + | Appetite regulation |
| MC5R | − | + | Exocrine function |
| Opioid receptors | − | ± | Analgesia |
GHRP-6’s broader receptor profile, particularly its activity at CD36 and melanocortin receptors, produces additional physiological effects beyond GH release that are not seen with GHRP-2.
| Parameter | GHRP-2 | GHRP-6 |
|---|
| ED50 for GH release | ~0.3 mcg/kg | ~1 mcg/kg |
| Typical dose | 100–300 mcg | 100–300 mcg |
| Peak GH (ng/mL) | 40–80 | 30–60 |
| Time to peak | 15–30 min | 15–30 min |
| Duration of GH pulse | 2–3 hrs | 2–3 hrs |
| IGF-1 elevation | +25–40% | +20–35% |
| Characteristic | GHRP-2 | GHRP-6 |
|---|
| Pulse amplitude | High | Moderate |
| Pulse duration | 2–3 hrs | 2–3 hrs |
| Basal GH effect | Minimal | Mild elevation |
| Synergy with GHRH | Strong | Moderate |
| Refractoriness | Develops at high doses | Develops at high doses |
| Parameter | GHRP-2 | GHRP-6 |
|---|
| ACTH elevation | Minimal | Significant |
| Cortisol elevation | Minimal | Moderate |
| Mechanism | Minimal MC2R activity | Direct MC2R agonism |
| Clinical significance | Low | Moderate (dose-limiting) |
GHRP-6’s MC2R activity produces clinically meaningful cortisol elevation, particularly at higher doses, which can confound hormonal assessments and produce Cushing-like side effects. GHRP-2’s minimal MC2R activity makes it the preferred choice for GH stimulation testing.
| Parameter | GHRP-2 | GHRP-6 |
|---|
| Prolactin elevation | Mild | Moderate |
| Mechanism | GHS-R1a (indirect) | GHS-R1a + direct |
| Clinical significance | Low | Moderate |
| Parameter | GHRP-2 | GHRP-6 |
|---|
| Appetite effect | Mild stimulation | Strong stimulation |
| Mechanism | GHS-R1a (hypothalamic) | GHS-R1a + MC4R + CD36 |
| Duration | Short (1–2 hrs) | Longer (3–4 hrs) |
GHRP-6’s stronger appetite stimulation is attributed to its broader receptor profile, including CD36-mediated lipid sensing and MC4R-mediated hypothalamic effects.
| Agent | Suitability | Rationale |
|---|
| GHRP-2 | Preferred | Minimal off-target effects; clean GH response |
| GHRP-6 | Less preferred | Cortisol/ACTH elevation confounds interpretation |
GHRP-2 is used as a diagnostic GH stimulation agent in some centers, though it is not FDA-approved for this indication. Its cleaner receptor profile produces a more interpretable GH response.
| Parameter | GHRP-2 | GHRP-6 |
|---|
| GH restoration | Effective | Effective |
| IGF-1 normalization | Effective | Effective |
| Cortisol disturbance | Minimal | Moderate |
| Prolactin disturbance | Mild | Moderate |
| Appetite effects | Mild | Strong |
| Preference | First-line | Second-line |
| Parameter | GHRP-2 | GHRP-6 |
|---|
| Lean mass gain | +2–4 kg over 12 weeks | +2–3 kg over 12 weeks |
| Fat mass loss | -1–3 kg over 12 weeks | -1–2 kg over 12 weeks |
| Cortisol impact on results | Minimal | May attenuate benefits |
| Parameter | GHRP-2 | GHRP-6 |
|---|
| Collagen synthesis | Moderate | Strong (CD36-mediated) |
| Angiogenesis | Moderate | Moderate |
| Anti-inflammatory | Mild | Moderate |
| Unique mechanism | GH-dependent | GH + CD36-dependent |
GHRP-6’s CD36 activity may confer additional tissue repair benefits through fatty acid transport and collagen synthesis, though this mechanism is not fully characterized.
| Parameter | GHRP-2 | GHRP-6 |
|---|
| Half-life | 15–30 min | 15–30 min |
| Bioavailability (SC) | ~100% | ~100% |
| Metabolism | Hepatic peptidases | Hepatic peptidases |
| Dosing frequency | 1–3× daily | 1–3× daily |
| Oral activity | None | None |
| Side Effect | GHRP-2 | GHRP-6 |
|---|
| Cortisol elevation | Minimal | Moderate |
| Prolactin elevation | Mild | Moderate |
| ACTH elevation | Minimal | Moderate |
| Appetite stimulation | Mild | Strong |
| Water retention | Mild | Mild |
| Joint pain | Occasional | Occasional |
| Glucose elevation | Mild, transient | Mild, transient |
| Injection site reactions | Common | Common |
| Clinical Scenario | Preferred Agent |
|---|
| GH stimulation testing | GHRP-2 (cleaner profile) |
| GH deficiency treatment | GHRP-2 (fewer off-targets) |
| Body composition improvement | Either (GHRP-2 preferred) |
| Tissue repair (musculoskeletal) | GHRP-6 (CD36 effects) |
| Appetite stimulation (cachexia) | GHRP-6 (stronger effect) |
| Cost-sensitive settings | Either (similar cost) |
| Patients on cortisol monitoring | GHRP-2 (minimal cortisol effect) |
GHRP-2 and GHRP-6 both activate GHS-R1a to stimulate GH release, but their receptor selectivity profiles differ significantly. GHRP-2 demonstrates high GHS-R1a selectivity with minimal off-target effects at ACTH, cortisol, and melanocortin receptors, making it the preferred agent for diagnostic testing and therapeutic GH replacement. GHRP-6 exhibits broader receptor activity, particularly at CD36 and MC2R, producing stronger appetite stimulation and additional tissue repair effects but also causing more cortisol and prolactin elevation. The choice between them depends on whether selectivity (GHRP-2) or pleiotropic effects (GHRP-6) are preferred for the clinical indication.
