Ipamorelin

Ipamorelin (Aib-His-D-2-Naphthylalanine-D-Phe-Lys-NH2) is a synthetic pentapeptide and the most GHS-R1a-selective growth hormone secretagogue characterised. Developed by Raun et al. (European Journal of Endocrinology, 1998) specifically to address the selectivity limitations of first- and second-generation GHRPs (GHRP-6, GHRP-2, Hexarelin), Ipamorelin achieves equivalent GH-releasing potency through GHS-R1a agonism without measurable off-target ACTH, cortisol, prolactin, or aldosterone stimulation at research concentrations.

GHS-R1a (the ghrelin receptor, GHSR gene) is a class A GPCR expressed at highest density on pituitary somatotrophs and hypothalamic arcuate nucleus neurons. It was cloned by Howard et al. (Science, 1996) as an orphan receptor using synthetic GHRPs as pharmacological probes — the receptor was identified before its endogenous ligand. Ghrelin (Kojima et al., Nature, 1999), discovered three years later, is the 28 amino acid endogenous GHS-R1a agonist requiring an unusual octanoyl modification at Ser3 for receptor activation. Ipamorelin mimics ghrelin's GHS-R1a pharmacology through its D-2-Naphthylalanine residue, which occupies the hydrophobic pocket in GHS-R1a's transmembrane bundle that normally accommodates the octanoyl chain — providing full GHS-R1a agonism without requiring a fatty acid modification.

GHS-R1a couples to Gq/11, activating phospholipase C-beta upon Ipamorelin binding. PLCbeta cleaves PIP2 into IP3 (triggering calcium release from ER via IP3 receptors) and DAG (activating PKC isoforms). The calcium transient generated by IP3/IP3R activity in pituitary somatotrophs drives GH secretory granule exocytosis through calcium-sensitive SNARE protein activation — a mechanism entirely distinct from the Gs/cAMP/PKA pathway activated by GHRHR. This mechanistic orthogonality is the research rationale for combining Ipamorelin with CJC-1295 No DAC: two receptors, two second messenger systems, convergent GH release producing additive-to-synergistic effects.

GHS-R1a demonstrates approximately 50% constitutive (ligand-independent) activity — unusually high among GPCRs. This basal signalling contributes to resting GH pulsatility and has important implications for research design: vehicle-treated control wells show GHS-R1a-dependent basal GH release above true zero. Ipamorelin as a full agonist maximises activity above this constitutive baseline; inverse agonists (compounds that suppress constitutive activity) can reduce GH release below basal levels.

The GHS-R1a also functions as a GPCR heterodimer partner for dopamine D1 receptor (DRD1) in the striatum, forming GHS-R1a:DRD1 heteromers that modulate dopamine reward signalling. This heteromerisation provides a molecular mechanism connecting the ghrelin system to reward and motivational circuits — a dimension of GHS-R1a biology that Ipamorelin can be used to probe in neuronal models.

Beyond GH release, GHS-R1a activation in hypothalamic NPY/AgRP neurons promotes food intake signalling. Ipamorelin at GH-releasing concentrations produces minimal appetite stimulation compared to GHRP-6 — making it the preferred tool when isolated GHS-R1a pharmacology without appetite confounds is required.

Research applications: GH secretion from primary pituitary cells (ELISA, sampling at 15-minute intervals); GHS-R1a binding assays ([125I]-ghrelin displacement or [35S]-GTPgammaS); calcium imaging in somatotrophs (Fura-2 or GCaMP6 reporters); constitutive activity characterisation using inverse agonists alongside Ipamorelin; and combination pharmacology with CJC-1295 No DAC in dual-receptor GH axis research.

MW: 711.85 g/mol. CAS: 170851-70-4. Molecular formula: C38H49N9O5. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.

GHS-R1a constitutive activity research note: approximately 50% of maximal GHS-R1a activity is constitutive in the absence of ligand. Vehicle control wells therefore show substantial basal GH release reflecting constitutive receptor activity plus somatostatin inhibitory tone — not experimental noise. Ipamorelin as full agonist maximises signalling above this constitutive baseline. For research requiring suppression of constitutive GHS-R1a activity, use an inverse agonist (such as [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-Substance P or specific GHS-R1a inverse agonists) alongside Ipamorelin to define the full agonist-to-inverse agonist pharmacological range. MW: 711.85 g/mol. CAS: 170851-70-4. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.