GH Secretagogue

Growth hormone secretagogues (GHS) are the pharmacological class that drives pulsatile GH release by acting on two distinct receptors: GHSR (ghrelin receptor, Gq/11-coupled) and GHRH-R (class B GPCR, Gs-coupled). They preserve physiological GH pulsatility and feedback inhibition - the key advantage over direct GH administration, which causes receptor downregulation. The GHS field generated the most advanced peptide pharmacophores for GH deficiency, cachexia, HIV lipodystrophy, and anti-aging research. Two peptide GHS have regulatory approval (macimorelin, tesamorelin); several are in active Phase 2/3 trials as of 2025.

Ghrelin (28 aa, n-octanoyl at Ser3) is the endogenous GHSR agonist; octanoylation by GOAT is required for receptor binding (Ki ~1 nM; des-acyl ~34 μM). Synthetic GHRPs (GHRP-6: His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂; GHRP-2; hexarelin) established the pharmacophore - D-amino acids in positions 1 or 2, aromatic at position 3, Lys at C-terminus. GHSR-1a couples to Gq/11 → PLC → IP3/Ca²⁺ → GH exocytosis, synergizing with GHRH through convergent intracellular signals. GHRH-R (on pituitary somatotrophs) couples to Gs → cAMP → PKA → Ca²⁺ influx → GH release. Sermorelin (GHRH 1-29 amide) and tesamorelin (GHRH 1-44 with N-terminal trans-3-hexenoyl group) are the peptide GHRH-R agonists. Somatostatin inhibits both pathways. GH pulse amplitude is highest during fasting and deep sleep; GHS compounds amplify existing pulses rather than driving continuous secretion. GOAT inhibition (blocking ghrelin octanoylation) is an emerging counter-strategy for obesity.

Tesamorelin (GHRH analog) is FDA-approved for HIV-associated lipodystrophy abdominal fat reduction. Macimorelin (oral GHSR agonist) is FDA-approved as a GH deficiency diagnostic agent. Anamorelin (GHSR agonist) is approved in Japan for cancer cachexia/anorexia. Sermorelin was approved then discontinued. Ibutamoren/MK-677 (oral non-peptide GHSR agonist) has extensive clinical data showing sustained GH/IGF-1 elevation, muscle mass gains, and improved sleep architecture but remains unapproved and is WADA-prohibited. LUM-201 (ibutamoren analog, oral) is in Phase 3 for pediatric GH deficiency (OraGrowtH trial). CJC-1295 (GHRH 1-29 with drug affinity complex for week-long half-life) is a widely studied research compound. For peptide research, the tractable recipes are: tesamorelin analogs with extended fatty acid modifications for once-weekly dosing; GHRP-2/hexarelin variants with backbone N-methylation for oral bioavailability; GHSR biased agonists favoring Gq/Ca²⁺ over β-arrestin to sustain GH pulse amplitude; and dual GHRH/ghrelin mimetics that simultaneously activate both axes for maximum GH output in GH deficiency treatment.