MELANOTAN2.XYZ explains one synthetic melanocortin peptide, its chemistry and the rules around it. There is no shop here.
Melanotan 2
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Overview

What is Melanotan 2?

Scope of this page: We describe the molecule and its pharmacology. There is no information here on amounts, preparation or use in people.

Melanotan 2 is a peptide of seven amino acids made by chemical synthesis. It copies the middle section of α-MSH, a 13-amino-acid hormone cut from the larger precursor protein pro-opiomelanocortin (POMC). That middle section carries the four residues His-Phe-Arg-Trp, the motif that melanocortin receptors recognise.

Reading the formula

The full name is written Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2. Every part of that string records a design decision:

  • Ac- and -NH2: caps on both ends that shield the peptide from enzymes which nibble at free chain ends.
  • Nle (norleucine): stands in for methionine, which oxidises easily, with a stable look-alike.
  • D-Phe: the mirror-image form of phenylalanine. This one swap, first reported in 1980, made α-MSH analogues much more potent and longer-acting.
  • cyclo[Asp … Lys]: the side chains of aspartic acid and lysine are joined by an amide, or lactam, bond. Six of the seven residues end up in the ring; norleucine forms a short tail.

Why build a ring?

A short linear peptide flexes through countless shapes and is quickly cut by enzymes. Locking it into a ring holds the receptor-binding residues close to the shape the receptor prefers. In the original Arizona experiments ring size was decisive: a 23-membered ring gave the strongest and most prolonged activity, while smaller rings lost most of it.

The melanocortin receptor family

Humans have five melanocortin receptors, numbered MC1R to MC5R. They sit in the cell membrane and signal mainly by raising cyclic AMP inside the cell.

  • MC1R: found chiefly on melanocytes, the pigment cells of skin and hair, and on some immune cells.
  • MC2R: the adrenal receptor for ACTH. It responds to ACTH only, so Melanotan 2 does not act on it.
  • MC3R and MC4R: concentrated in the brain, where they belong to the circuits that regulate energy balance and several behaviours.
  • MC5R: spread through peripheral tissues, including exocrine glands.

Melanotan 2 activates MC1R, MC3R, MC4R and MC5R with high potency. That lack of selectivity explains both its usefulness as a laboratory tool and the wide spread of effects reported in people.

Related compounds

  • Afamelanotide (Melanotan 1): the linear analogue [Nle4, D-Phe7]-α-MSH, also called NDP-MSH. Unlike Melanotan 2 it was developed into an approved medicine for a rare light-sensitivity disorder.
  • Bremelanotide (PT-141): derived from Melanotan 2. It has the same ring but ends in a free carboxylic acid instead of an amide.
  • SHU9119: Melanotan 2 with the bulkier D-naphthylalanine in place of D-Phe. That substitution turns it into a blocker of MC3R and MC4R, and it became the standard antagonist partner in experiments.

Summary

  • A seven-residue ring peptide modelled on the core of α-MSH.
  • Activates four of the five melanocortin receptors, but not MC2R.
  • A sibling of afamelanotide and the parent of bremelanotide and SHU9119.
  • A research chemical, not an approved medicine.