The numbers

The binding matrix: how tightly each ligand holds each receptor

A cited quantitative map of melanocortin pharmacology — the binding affinity and potency of every catalogued ligand at MC1R through MC5R, drawn from the IUPHAR/BPS Guide to Pharmacology. The selectivity story, in one figure.

By melanocortin.com editorialLast updated 2026

The whole system rendered as numbers — every signal and every brake, measured against the five switches it speaks to.

Most of this site describes melanocortin pharmacology in words — selective,superpotent, broad. This page puts the numbers behind those words in one place. It is a quantitative map of how tightly each ligand binds each of the five receptors, assembled from the IUPHAR/BPS Guide to Pharmacology — the field's curated pharmacology database, where every value traces to a primary paper.

Binding strength here is a p-value: the negative logarithm of the molar affinity. It is a compact way to write very small concentrations — a p of 9 means about 1 nanomolar, a p of 6 about 1 micromolar — and, usefully, higher means tighter. In the figure each disc is sized by that number, so the eye reads potency directly. For the qualitative version — who is an agonist, partial agonist or antagonist where — see the interactive receptor–ligand explorer.

The melanocortin receptor binding matrixBinding strength of each melanocortin ligand at receptors MC1R through MC5R. Each disc is sized by affinity (bigger = tighter binding); filled discs are agonists that activate the receptor, rings are antagonists that block it, and blank cells have no curated value. MC2R responds almost only to ACTH.MC1Rskin · pigmentMC2Radrenal · cortisolMC3Renergy balanceMC4Rappetite · satietyMC5Rexocrine glandsα-MSHbroad agonist8.4·8.0–8.47.4–8.06.9γ-MSHMC3R-preferring··8.5··ACTHthe only MC2R ligand8.69.8ᵐ7.16.25.0Afamelanotidesuperpotent, broad10.0·8.98.5–8.89.0Melanotan IIbroad agonist9.4·8.38.2–8.89.0BremelanotideMC4R-preferring8.2·7.39.67.8SetmelanotideMC4R drug, broad binder8.4·8.08.76.4AgRPblocks MC3R/MC4R··7.79.36.5Agouti (ASIP)the pigment brake8.6ᵐ·6.7ᵐ7.3ᵐ4.9ᵐ= binding strength (bigger = tighter)agonistantagonistValues are pKi / pKd / pIC50 (−log₁₀ M) curated by IUPHAR/BPS GtoPdb; human unless ᵐ (mouse); blank = no curated value.

Reading the matrix

A few things jump out that prose alone tends to bury. MC2R is almost a blank column. Alone among the five, it answers essentially only to ACTH and turns away the MSH peptides that light up the others — the single clearest fact in the whole grid, and the reason MC2R sits apart in the family.

The engineered peptides are the tightest binders. Afamelanotide — the α-MSH analogue NDP-α-MSH — is the biggest disc on the board, roughly 0.1 nM at MC1R and sub-nanomolar across the MSH receptors. Two amino-acid substitutions to α-MSH buy an order-of-magnitude jump in grip; the grey-market peptide Melanotan II sits just below it, similarly broad. That breadth is the point: none of these is subtle about selectivity.

Where a drug is tight is where it works. Bremelanotide binds MC4R most tightly of all (~0.25 nM), which is exactly the receptor behind its central, desire-related effect. Setmelanotide is more surprising: by raw binding it grips MC1R, MC3R and MC4R at broadly similar strength, yet it is used as an MC4R medicine — a reminder that binding and what the receptor then doesare not the same measurement (the difference is functional and, for setmelanotide, signalling-biased).

The brakes bind too. AgRP and agouti (ASIP) appear as rings, not discs: they hold MC3R/MC4R and MC1R tightly but to block, not to activate. AgRP's grip on MC4R (~0.5 nM) rivals the best agonists — the hunger signal and the satiety signal fight for the same switch at comparable strength, which is much of why the appetite rheostat is so finely balanced.

The values, with sources

Every number below is a curated affinity (pKi/pKd) or functional potency (pIC50) with its approximate molar value and a link to the primary paper. Values are for the human receptor unless marked ᵐ (mouse).

LigandMC1RMC2RMC3RMC4RMC5R
α-MSH8.41≈4.0 nM—8.0–8.42≈6.3 nM7.4–8.03≈20 nM6.91≈1.3e+2 nM
γ-MSH——8.52≈3.2 nM——
ACTH8.64≈2.5 nM9.8ᵐ5≈0.16 nM7.14≈79 nM6.26≈6.3e+2 nM5.04≈10 µM
Afamelanotide10.01≈0.10 nM—8.93≈1.3 nM8.5–8.83≈2.2 nM9.01≈1.0 nM
Melanotan II9.41≈0.40 nM—8.33≈5.0 nM8.2–8.87≈3.2 nM9.01≈1.0 nM
Bremelanotide8.28≈6.3 nM—7.38≈50 nM9.68≈0.25 nM7.88≈16 nM
Setmelanotide8.49≈4.0 nM—8.09≈10 nM8.79≈2.0 nM6.49≈4.0e+2 nM
AgRP——7.710blocks · ≈20 nM9.311blocks · ≈0.50 nM6.512blocks · ≈3.2e+2 nM
Agouti (ASIP)8.6ᵐ13blocks · ≈2.5 nM—6.7ᵐ14blocks · ≈2.0e+2 nM7.3ᵐ14blocks · ≈50 nM4.9ᵐ14blocks · ≈13 µM

Coloured values are antagonists/inverse agonists (blockers); plain values are agonists. ≈ value is the molar affinity implied by the p-value (109−p nM). Ranges are shown where the source gives one.

How to read these numbers — and how not to

These are representative literature values, not a meta-analysis. They mix binding affinities (pKi, pKd) with functional potencies (pIC50), and they come from different labs, assay systems and radioligands across three decades — so treat them as order-of-magnitude comparisons, not decimal-precise constants. Most are human; a few (marked ᵐ) are mouse, where human data were not curated. Two catalogued ligands are absent because no clean quantitative values are tabulated for them: β-MSH(a broad agonist) and dersimelagon (a small molecule whose affinities are not publicly reported). Not medical advice. See the editorial standards.

Common questions

What does the binding matrix show?

How tightly each melanocortin ligand binds each of the five receptors (MC1R–MC5R). Each value is an affinity or potency from the IUPHAR/BPS Guide to Pharmacology, expressed as a p-value (the negative log of the molar concentration): higher means tighter binding, so a p of 9 is about 1 nanomolar and a p of 6 about 1 micromolar.

Why does MC2R look almost empty?

Because it is. MC2R is the odd receptor out: it responds essentially only to ACTH and ignores the MSH peptides that activate the other four. That single-ligand column is one of the clearest facts the matrix makes visible.

Which ligand binds most tightly?

Afamelanotide (the research peptide NDP-α-MSH) is the standout — roughly 0.1 nanomolar at MC1R and sub-nanomolar across the MSH receptors. That superpotency, engineered from just two amino-acid swaps to α-MSH, is exactly why it works as a drug.

Are agonists and antagonists shown the same way?

No. Filled discs are agonists that switch the receptor on; rings with a bar are antagonists (or inverse agonists) that block it — AgRP and agouti (ASIP), the system’s natural brakes. Binding strength is shown for both, because a blocker still has to bind to work.

Sources

All values were compiled from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding SD, et al. Nucleic Acids Res.2024;52:D1438–D1449; guidetopharmacology.org, accessed 18 Aug 2026), which curates each value from the primary literature below.

  1. 1.MacNeil DJ, Howard AD, Guan X et al. (2002) The role of melanocortins in body weight regulation. Eur J Pharmacol 440:141–57. PMID 12007532 ↗
  2. 2.Oosterom J, Nijenhuis WA, Schaaper WM et al. (1999) Conformation of the core sequence in melanocortin peptides directs MC3/MC4 selectivity. J Biol Chem 274:16853–60. PMID 10358030 ↗
  3. 3.Adan RA, Szklarczyk AW, Oosterom J et al. (1999) Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors. Eur J Pharmacol 378:249–58. PMID 10493100 ↗
  4. 4.Schiöth HB, Muceniece R, Wikberg JE, Chhajlani V (1995) Characterisation of melanocortin receptor subtypes by radioligand binding. Eur J Pharmacol 288:311–17. PMID 7774675 ↗
  5. 5.Kapas S, Cammas FM, Hinson JP, Clark AJ (1996) Agonist and receptor binding properties of ACTH peptides using the cloned mouse ACTH receptor. Endocrinology 137:3291–4. PMID 8754753 ↗
  6. 6.Schiöth HB, Muceniece R, Wikberg JE (1996) Characterisation of the melanocortin 4 receptor by radioligand binding. Pharmacol Toxicol 79:161–5. PMID 8884876 ↗
  7. 7.Al-Obeidi F, Hruby VJ, Castrucci AM, Hadley ME (1989) Design of potent linear α-melanotropin 4-10 analogues. J Med Chem 32:174–79. PMID 2535874 ↗
  8. 8.Conde-Frieboes K, Thøgersen H, Lau JF et al. (2012) Characterization of long-acting, MC4R-selective α-MSH analogues. J Med Chem 55:1969–77. PMID 22335602 ↗
  9. 9.Kumar KG, Sutton GM, Dong JZ et al. (2009) Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient mice. Peptides 30:1892–900. PMID 19646498 ↗
  10. 10.Rosenfeld RD, Zeni L, Welcher AA et al. (1998) Characterization of bacterially expressed human agouti-related protein. Biochemistry 37:16041–52. PMID 9819197 ↗
  11. 11.Fong TM, Mao C, MacNeil T et al. (1997) ART (agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Commun 237:629–31. PMID 9299416 ↗
  12. 12.Yang YK, Thompson DA, Dickinson CJ et al. (1999) Characterization of agouti-related protein binding to melanocortin receptors. Mol Endocrinol 13:148–55. PMID 9892020 ↗
  13. 13.Lu D, Willard D, Patel IR et al. (1994) Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371:799–802. PMID 7935841 ↗
  14. 14.Kiefer LL, Veal JM, Mountjoy KG, Wilkison WO (1998) Melanocortin receptor binding determinants in the agouti protein. Biochemistry 37:991–7. PMID 9454589 ↗