Ipamorelin: Mechanism of Action
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Mechanism of Action
Ipamorelin activates the GHS-R1a (ghrelin receptor) on pituitary somatotroph cells with an in vitro EC₅₀ of 1.3 ± 0.4 nmol/L and in vivo ED₅₀ of 2.3 nmol/kg (swine). Binding triggers phospholipase C (PLC) activation via Gα₁₁/q → IP3 → intracellular Ca²⁺ release → GH vesicle exocytosis — a pathway distinct from GHRH's cAMP signaling.[1][2]
Receptor & Signaling Profile
| Target | Action | Downstream Effect |
|---|---|---|
| GHS-R1a (Ghrelin Receptor) | Selective agonist | PLC → IP3 → Ca²⁺ → GH vesicle exocytosis |
| cAMP (Synergistic) | Enhances pre-stimulated adenylyl cyclase | Synergistic GH release when combined with GHRH |
| Enteric Cholinergic Neurons | Activates excitatory neurons (atropine/TTX-sensitive) | Accelerates gastric motility and emptying |
Ipamorelin's selectivity is exceptional: it does NOT stimulate ACTH, cortisol, FSH, LH, prolactin, or TSH — even at doses 200× the ED₅₀. Additionally, chronic administration does not desensitize somatotrophs, unlike GHRH which induces homologous down-regulation.[1][7]
In humans, Ipamorelin exhibits linear pharmacokinetics with a T½ of ~2 hours, SC₅₀ of 214 nmol/L, and triggers a single episodic GH burst peaking at 0.67 hours post-administration.[2]
vs. Related Compounds
| Feature | Ipamorelin | GHRP-6 / GHRP-2 | GHRH |
|---|---|---|---|
| Selectivity | HIGH — GH only | LOW — GH + ACTH + cortisol + prolactin | Selective for GH |
| Desensitization | NO | Partial | YES (homologous) |
| Primary Signaling | PLC / Ca²⁺ | PLC / Ca²⁺ | cAMP |
| Half-Life (Human) | ~2 hours | Shorter (5× faster clearance) | Minutes |
References
- Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology. 1998;139(5):552-561.
- Gobburu JVS, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research. 1999;16(9):1412-1416.
- Johansen PB, Nowak J, Skjaerbaek C, et al. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Hormone & IGF Research. 1999;9(2):106-113.
- Venkova K, Mann W, Nelson R, Greenwood-Van Meerveld B. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. JPET. 2009;329(3):1110-1116.
- Greenwood-Van Meerveld B, Tyler K, Mohammadi E, Pietra C. Efficacy of ipamorelin on gastric dysmotility in a rodent model of postoperative ileus. Journal of Experimental Pharmacology. 2012;4:149-155.
- Beck DE, Sweeney WB, McCarter MD. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014;29(12):1527-1534.
- Jiménez-Reina L, Cañete R, de la Torre MJ, Bernal G. Chronic in vivo Ipamorelin treatment stimulates body weight gain and growth hormone release in vitro in young female rats. European Journal of Anatomy. 2002;6(1):37-45.
- Svensson J, Lall S, Dickson SL, Jansson JO. The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. Journal of Endocrinology. 2000;165:569-577.
- Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL. Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. BBRC. 2001;280(1):132-138.
- Adeghate E, Ponery AS. Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats. Neuro Endocrinology Letters. 2004;25(6):403-406.
- Johansen PB, Hansen KT, Andersen JV, Johansen NL. Pharmacokinetic evaluation of ipamorelin with emphasis on nasal absorption. Xenobiotica. 1998;28(11):1083-1092.
- Andersen NB, Malmlöf K, Johansen PB, Oxlund H. The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats. Growth Hormone & IGF Research. 2001;11(5):266-272.
- Hansen TK, Ankersen M, Raun K, Hansen BS. Highly Potent Growth Hormone Secretagogues: Hybrids of NN703 and Ipamorelin. Bioorganic & Medicinal Chemistry Letters. 2001;11(14):1915-1918.
- Lu Z, Ngan MP, Liu JYH, Rudd JA. The GHS-R1a agonists anamorelin and ipamorelin inhibit cisplatin-induced weight loss in ferrets. Physiology & Behavior. 2024.
- Sinha DK, Balasubramanian A, Tatem AJ, et al. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational Andrology and Urology. 2020;9(Suppl 2):S149-S159.
- Thøgersen H, Johansen NL, Lau J, et al. A New Series of Highly Potent Growth Hormone-Releasing Peptides Derived from Ipamorelin. Journal of Medicinal Chemistry. 1998;41.
- Mohammadi E, Bhatt V, Bhatt AB, Pietra C, Greenwood-Van Meerveld B. Ipamorelin attenuates visceral and somatic nociception through peripheral ghrelin receptor mechanisms. 2020.
- U.S. Food & Drug Administration. FDA Evaluation of Ipamorelin-Related Bulk Drug Substances. FDA Pharmacy Compounding Advisory Committee. 2024.
- World Anti-Doping Agency. WADA Prohibited List — S2: Peptide Hormones, Growth Factors, Related Substances, and Mimetics. 2024.
- Polvino WJ. Methods of treatment using a ghrelin receptor agonist. US Patent 8,039,456 B2.
- Thøger Nielsen K, et al. Validated screening method for GH-releasing peptides using UHPLC-HRMS on dried blood spots. Drug Testing and Analysis. 2021.
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