A multi-receptor peptide agonist’s potency is not a property that travels with the sequence. It is the concentration–response of a named receptor, in a named expression system, measured with a named functional readout. Without those three pieces, EC50 values cannot be compared across receptors, and they should not be ranked as therapeutic benefit.
What an EC50 actually records
Receptor-specific activity is an assay result, not a sequence annotation. On 9 July 2026, James-Okoro and colleagues profiled 42 ligands at heterologously expressed human glucose-dependent insulinotropic polypeptide receptor (GIPR) with three readouts: cAMP accumulation, calcium mobilisation, and cAMP inhibition. Glicentin was the only non-proGIP-derived peptide to produce a cAMP response at GIPR (EC50 = 877 nM). No ligand-induced calcium mobilisation or cAMP inhibition was observed. The same peptide also activated human glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). Receptor-specific antibody blockade reduced potency 10- to 20-fold at all three receptors. Activity was conserved at rodent GIPRs, with reduced potency. The authors concluded that the high EC50 makes glicentin unlikely to act as a physiological GIPR ligand under basal conditions, and described it as a low-potency, cross-reactive agonist at GIPR, GLP-1R and GCGR.
That dataset is a practical map for multi-receptor tables. A peptide can register at several receptors and still be a low-potency, cross-reactive agonist rather than a designed dual agonist. A cAMP EC50 does not imply a calcium or inhibitory-cAMP signal at the same receptor. Antibody blockade is a receptor-assignment control: a 10- to 20-fold potency loss supports that the measured signal depended on the intended receptor, not that the ligand would occupy that receptor in tissue.
Designed multi-agonists still need the same discipline. On 18 June 2026, Kostadinova and colleagues used a modular polyethylene glycol scaffold to attach GLP-1 and amylin receptor agonists. Lead conjugates displayed balanced, low-picomolar potency at both receptors in cAMP assays and selective receptor-mediated internalisation in GLP-1 receptor-expressing cells. “Balanced” in that report is a statement about two cAMP curves in the systems used, plus trafficking observed in GLP-1R-expressing cells. It is not evidence of matched internalisation at both receptors, matched in vivo occupancy, or matched clinical contribution.
Even at a single GPCR, potency is interpretable only when activation is defined the same way for the test ligand and a peptide reference agonist. On 4 August 2026, Skiba and colleagues found that the nonpeptide AT1R agonist L-162,313 binds similarly to AT1R antagonists yet engages the same activation switches as peptide agonists; derivatives designed from that spatial map then showed the expected reduced or enhanced potency. That is a method point, not a multi-receptor result: holding receptor, activation definition, and assay constant is what made those potency shifts readable.
Expression partners, species, and what the number is not
Heterologous expression is not a fixed background. In the glicentin study, co-expression of RAMP2 or RAMP3 attenuated cAMP responses to GIPR-active ligands, including glicentin, but did not affect other ligands tested. Human versus rodent GIPR also changed potency. The same peptide sequence can therefore yield different EC50 values depending on which proteins are co-expressed and which ortholog is used.
Each receptor targeted by a multi-agonist still needs its own activity measurement in the same functional system. The glicentin work used a 42-ligand panel and receptor-specific antibodies; the dual-agonist conjugates were compared at both target receptors in cAMP. Neither abstract reports that those in-vitro ranks predict clinical effect sizes.
A review dated 1 August 2026 on the clinical potential of GIP notes that tirzepatide is a dual incretin receptor agonist that engages GLP-1R and GIPR, and that the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established. Dual engagement can be shown in cells; contribution to clinical outcomes cannot be read from whether one EC50 is picomolar and another is nanomolar.
As of literature captured on 3 October 2026, a specific remaining question is how to weight RAMP co-expression, species orthologs, and trafficking when a conjugate is described as balanced in cAMP but internalisation has been reported for only one of the two receptors.
What to record before comparing two potency values
| Item to record | What these abstracts illustrate |
|---|---|
| Receptor identity and species | Glicentin’s GIPR cAMP EC50 was 877 nM at human GIPR; potency was reduced at rodent GIPRs |
| Expression partners | RAMP2 or RAMP3 attenuated cAMP responses to GIPR-active ligands, including glicentin |
| Functional readout | cAMP detected glicentin at GIPR; calcium mobilisation and cAMP inhibition did not; dual-agonist leads were scored in cAMP, with internalisation only in GLP-1R-expressing cells |
| Specificity control | Receptor-specific antibodies reduced glicentin potency 10- to 20-fold at GIPR, GLP-1R and GCGR |
| Reference for activation | At AT1R, potency shifts were readable once nonpeptide agonists were mapped onto the same activation switches as peptide agonists |
| What the number is not | A rank of therapeutic benefit, or of each receptor’s clinical contribution |
Frequently Asked Questions
If a conjugate is “balanced” in cAMP, does that mean both receptors internalise equally?
No. Lead GLP-1/amylin conjugates showed balanced, low-picomolar potency at both receptors in cAMP assays; selective receptor-mediated internalisation was reported in GLP-1 receptor-expressing cells, not as a matched trafficking result at both receptors.
How should I treat a high-nanomolar EC50 at a second receptor?
In the glicentin study, an 877 nM GIPR cAMP EC50 plus activity at GLP-1R and GCGR supported calling glicentin a low-potency, cross-reactive agonist, and a basal physiological GIPR role unlikely. Magnitude belongs in the interpretation; it is not a therapeutic score.
Why do RAMPs matter if the peptide sequence is unchanged?
Co-expression of RAMP2 or RAMP3 attenuated cAMP responses to GIPR-active ligands, including glicentin, without affecting other ligands tested. The same sequence can therefore yield different potencies depending on which proteins are co-expressed.
Explore Further
Browse our research peptide catalog and review third-party lab reports & COAs for published batches.
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Research use only. The information above is provided for educational and laboratory research purposes only. The compounds discussed are not approved for human or veterinary use, diagnosis, treatment, or the prevention of any disease. Nothing here is medical advice.