Melanocortin Receptor Subtypes (MC1R–MC5R) in Peptide Research

The melanocortin receptors are a family of five G-protein-coupled receptors, MC1R through MC5R, that recognize α-melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH) and related peptides. Several compounds in the research library are ligands of this family, and closely related ligands can behave differently at each subtype. This overview follows the primary literature on how the receptors were identified, how synthetic ligands separate them, and what a receptor-bound structure shows.

Cloning the Receptor Family

Mountjoy et al. (1992) cloned the murine and human melanocyte-stimulating hormone receptors and a human ACTH receptor, and described them as defining a subfamily of receptors coupled to guanine nucleotide-binding proteins. Hruby et al. (1995) summarize what followed: after the MSH receptor (MC1R) and the ACTH receptor (MC2R), three additional receptors were identified, MC3R, MC4R and MC5R. In their account MC2R primarily recognizes only ACTH peptides, while the other four all recognize α-MSH and potent α-MSH agonists as well as ACTH. They describe MC3R and MC4R as expressed in the brain and MC5R as expressed across a number of peripheral tissues.

One Scaffold, Agonists and Antagonists

The ligands most often used to tell the subtypes apart share a cyclic lactam scaffold. Melanotan II (MT-II) is the cyclic agonist that Hruby et al. (1995) took as their starting point. Replacing the D-phenylalanine at position 7 with a bulky aromatic residue changed the pharmacology. The D-2-naphthylalanine analogue, catalogued in the library as SHU9119, was a potent antagonist at MC4R (pA2 9.3) and a less potent antagonist at MC3R (pA2 8.3), with minimal agonist activity at either, and a full agonist at MC1R and MC5R. The same paper reports that the D-p-chloro- and D-p-fluorophenylalanine analogues had no antagonist activity at any melanotropin receptor. A single position on one scaffold therefore separates agonism from antagonism, and does so differently at different subtypes.

Bednarek et al. (1999) mapped which residues of MT-II matter, measuring both binding and activation at human MC3R, MC4R and MC5R. Replacing histidine with alanine left affinity and agonist potency similar to MT-II. Replacing arginine with alanine gave a compound about 100-fold less potent, and replacing phenylalanine or tryptophan with alanine gave compounds that were inactive at micromolar concentrations. The retro, enantio and retro-enantio analogues lost potency significantly, which the authors read as showing a crucial role for side-chain topology.

Bremelanotide and the MC4R Structures

Bremelanotide (PT-141) belongs to the same scaffold: structurally it is the C-terminal free-acid form of MT-II. Zhang et al. (2021) determined cryo-electron microscopy structures of full-length MC4R in complex with Gs protein, bound in turn to α-MSH, afamelanotide, bremelanotide and the small-molecule ligand THIQ. They report a conserved binding mode for the peptidic agonists, and distinct molecular details of small-molecule agonist recognition that underlie receptor subtype selectivity.

An Agonist and an Antagonist as Paired Tools

Fan et al. (1997) used two of the lactam analogues together. Having identified cyclic melanocortin analogues that are potent agonists or antagonists of the neural MC3 and MC4 receptors, they paired the agonist MT-II with the antagonist SHU9119 in mouse feeding models to test whether the agouti peptide acts through hypothalamic melanocortin receptors. The antagonist blocked the effect of the agonist, and the authors concluded that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. The study is an example of using a matched agonist and antagonist to assign a function to a receptor population in an animal model. It is a statement about mouse neurobiology, not about any use of either compound.

Reading a Melanocortin Paper

• Which subtype was measured. A result at MC1R says nothing about MC4R: in Hruby et al. the same analogue is a full agonist at one and an antagonist at the other.
• Which species. Hruby et al. report values from a frog skin assay and from cloned mouse and human receptors, and the numbers differ between them.
• Binding or function. Bednarek et al. measured both. An affinity is not an agonist potency.
• Which molecule. MT-II and bremelanotide differ only at the C-terminus, an amide in one and a free acid in the other, which is about one dalton by mass.

Related Library Records

The research library holds identity monographs for the ligands named here and for their relatives: α-MSH, afamelanotide, Melanotan II, bremelanotide, SHU9119, THIQ, setmelanotide, cosyntropin and KPV. The receptor family has its own page at melanocortin receptors.

References

1. Mountjoy KG, Robbins LS, et al. The cloning of a family of genes that encode the melanocortin receptors. Science 1992. PMID: 1325670.
2. Hruby VJ, Lu D, et al. Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995. PMID: 7658432.
3. Fan W, Boston BA, et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997. PMID: 8990120.
4. Bednarek MA, Silva MV, et al. Structure-function studies on the cyclic peptide MT-II, lactam derivative of alpha-melanotropin. Peptides 1999. PMID: 10447101.
5. Zhang H, Chen LN, et al. Structural insights into ligand recognition and activation of the melanocortin-4 receptor. Cell Res 2021. PMID: 34433901.

This article summarizes publicly available research for educational purposes and does not constitute medical advice, a therapeutic claim, or a recommendation for human use. Products referenced are sold for laboratory research use only.