Ghrelin Receptor Interactions
How GH secretagogues interact with ghrelin receptors (GHS-R1a).
Ghrelin Receptor Basics
The ghrelin receptor (GHS-R1a) is the main target of the GH-releasing peptides and MK-677. The receptor binding overview covers other targets.
Receptor Characteristics
| Feature | Description |
|---|---|
| Type | G protein-coupled receptor |
| Location | Pituitary, hypothalamus, GI tract |
| Endogenous ligand | Ghrelin |
| Synthetic ligands | GHRPs, MK-677 |
In cell studies, the receptor signals strongly even with nothing bound to it (Holst 2003). Nobody has measured whether this matters in people.
Signaling Pathway
| Step | Event | Outcome |
|---|---|---|
| 1 | Ligand binding | Receptor activation |
| 2 | G protein coupling | Signal transduction |
| 3 | Ca2+ release | Intracellular calcium |
| 4 | GH release | Pituitary secretion |
Peptide Receptor Interactions
GHRP Series
| Peptide | ACTH/cortisol | Appetite effect |
|---|---|---|
| GHRP-6 | Raised (swine) | Strong hunger (users) |
| GHRP-2 | Raised (swine) | Moderate hunger (users) |
| Hexarelin | Cortisol raised (human, IV) | Unclear |
| Ipamorelin | Not raised (swine) | Minimal (users) |
Non-Peptide
| Compound | Receptor Affinity | Half-life | Oral Activity |
|---|---|---|---|
| MK-677 | High | Long | Yes |
| Anamorelin | High | Long | Yes |
Receptor Selectivity Importance
Why Selectivity Matters
Ipamorelin's reputation rests on a 1998 study in rats and swine (Raun 1998). It matched GHRP-6 for GH release but didn't raise ACTH or cortisol, even at 200 times its effective dose. In swine, no compound changed prolactin. MK-677 isn't fully selective: cortisol rose over a 2-year trial in older adults (Nass 2008).
Practical Implications
| Goal | Common user pick | Caveat |
|---|---|---|
| Maximum GH | GHRP-6/Hexarelin | Hexarelin response fades |
| Clean release | Ipamorelin | Animal data only |
| Appetite during bulk | GHRP-6 | User reports |
| Cutting | Ipamorelin | No fat-loss trial |
Receptor Desensitization
| Factor | What's known | Evidence |
|---|---|---|
| Continuous exposure | Users cycle to avoid fading | User reports |
| Hexarelin | GH response down about 45% at 16 weeks; recovered after 4 weeks off | 12 older adults (Rahim 1998) |
| MK-677 | IGF-1 stayed raised for 2 years | One RCT |
| Ipamorelin | Said to fade slowly | No long-term data |
What we still don't know
No human study has tested ipamorelin's cortisol selectivity. Released GH then acts on its own receptor, covered in growth hormone receptor signaling.
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References
- High constitutive signaling of the ghrelin receptor: identification of a potent inverse agonist (Molecular Endocrinology, 2003)
- Ipamorelin, the first selective growth hormone secretagogue (European Journal of Endocrinology, 1998)
- Does desensitization to hexarelin occur? 16-week study in 12 healthy older adults (Growth Hormone & IGF Research, 1998)
- Acute cardiovascular and hormonal effects of GH and hexarelin in humans (Journal of Endocrinological Investigation, 1999)
- MK-677 2-year randomized trial in healthy older adults (Annals of Internal Medicine, 2008)