Melanotan I (Afamelanotide) vs Melanotan II (MT-II)

Melanotan I (Afamelanotide)

Melanotan I, also known as afamelanotide, is a 13-residue synthetic analogue of alpha-melanocyte-stimulating hormone (α-MSH). It differs from the natural hormone at two positions: norleucine takes the place of methionine at position 4, and the phenylalanine at position 7 is the D-isomer. The parent hormone is one of the melanocortins, a family of peptides cut from the precursor pro-opiomelanocortin (POMC) that also includes adrenocorticotropic hormone (ACTH) and β- and γ-MSH. The analogue has been characterised in receptor-binding and cell assays and in animal studies, and it has also been the subject of human clinical research. Melanotan II is a separate, shorter and cyclic analogue.

Melanotan II (MT-II)

Melanotan II is a synthetic cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone (α-MSH), closed by a lactam bridge. The ring is formed by an amide bond between the side chains of aspartic acid and lysine, and it encloses His-D-Phe-Arg-Trp, the receptor-binding core of the melanocortin peptides. With an acetylated norleucine outside the ring and an amidated C-terminus, it is much shorter and more conformationally constrained than the 13-residue parent hormone. It is widely used in rodent research as a reference melanocortin agonist, and human data are limited to a few small early studies. Bremelanotide (PT-141) differs from it only at the C-terminus.

How Melanotan I (Afamelanotide) acts

The melanocortin receptors are five G-protein-coupled receptors, MC1R to MC5R, that signal mainly through Gs, adenylyl cyclase and cyclic AMP. Afamelanotide has been reported to bind MC1R with high affinity and to act at MC3R, MC4R and MC5R as well, so it is not selective for a single subtype. Its two substitutions sit at deliberate points: norleucine removes a methionine that oxidises readily, and the D-phenylalanine lies within the His-Phe-Arg-Trp sequence shared by the natural melanocortin peptides, where it has been reported to raise receptor affinity and resistance to enzymatic breakdown. MC1R is expressed in skin and on several immune-cell types, and MC4R mainly in the brain.

How Melanotan II (MT-II) acts

Melanotan II has been reported to act as an agonist at MC1R, MC3R, MC4R and MC5R, and it is regarded as non-selective among them. Each is a G-protein-coupled receptor that signals mainly through Gs and cyclic AMP. MC3R and MC4R are expressed in the hypothalamus and other brain regions, which is why the peptide has been used so often in rodent work on central melanocortin signalling. At those two receptors its action runs opposite to that of agouti-related peptide, an endogenous antagonist and inverse agonist. The lactam ring is thought to hold the core residues in a turn conformation that favours receptor binding.

The records side by side

• Type: Melanotan I (Afamelanotide), Melanocortin receptor agonist (α-MSH analog); Melanotan II (MT-II), Cyclic heptapeptide (α-MSH analog)
• Length: Melanotan I (Afamelanotide), 13 amino acids; Melanotan II (MT-II), 7 amino acids
• Molecular weight: Melanotan I (Afamelanotide), 1646.8 g/mol; Melanotan II (MT-II), 1024.2 g/mol
• Molecular formula: Melanotan I (Afamelanotide), C78H111N21O19; Melanotan II (MT-II), C50H69N15O9

Reading a comparison

A comparison places two records side by side; it does not merge them. Each description above is drawn from that compound's own record, and the two were not necessarily characterised by the same methods, at the same time, or to the same level of detail. Before comparing any attribute, it is worth establishing that both records describe the substance you think they describe — names are not identifiers, and two entries sharing a name can differ in salt form, stereochemistry or the convention used to state a mass. Where a figure carries no method beside it, the comparison is between two reported numbers rather than between two measurements.