Melanotan II

Mechanism (as reported)

A study characterizing MT-II in terms of receptor targeting describes MT-II as a melanotropin (melanocortin) receptor-targeting agent (PMID 37478579). Another paper describes MT-II as an unselective agonist of human melanocortin receptors (hMCRs) and discusses replacing its lactam cyclization to tune binding/functional selectivity (PMID 35188390).

Key findings (each cites a source)

• Melanotan-II (MT-II) is described as a lactam-bridged cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone (alpha-MSH) with a structure reported as Ac-Nle4-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10 alpha-MSH4-10-NH2. [PMID 8637402]
• In vitro characterization in the clinical pilot report describes MT-II as having “superpotent melanotropic activity.” [PMID 8637402]
• In a zebrafish model, zebrafish fed a short-term high-fat diet showed recognition memory impairment, elevated anxiety levels, and reduced exploratory propensity after three weeks, and these high-fat diet-induced abnormalities were reported to be reversed by MT-II treatment. [PMID 37478579]
• A pilot phase-I study in 3 normal male volunteers reported that MT-II produced tanning activity in humans, with increased pigmentation observed 1 week after dosing ended. [PMID 8637402]
• In that phase-I pilot study, Grade II somnolence and fatigue were reported for one subject at a higher dose level, along with mild nausea at most MT-II dose levels; a stretching/yawning complex correlated with intermittent spontaneous penile erections, as described in the report. [PMID 8637402]
• Research using MT-II as a parent compound described an approach (“Chemical Linkage of Peptide onto Scaffolds”) that replaced MT-II’s lactam cyclization with xylene-derived thioethers and reported binding affinities spanning low nanomolar to sub-micromolar ranges; the paper further reported functional selectivity toward hMC1R for a specific designed compound relative to MT-II. [PMID 35188390]
• A peptide chemistry study reported efficient condensation of a 5-hydroxypyrroloindoline with cysteine-thiol or tryptophan-indole to form tryptathionine or 2,2'-bis-indole “staple” constructs applicable to α-MSH/MT-II-related targeting using α-MSH for investigating chemoselectivity and affinity; it reported nanomolar Ki values and one sub-nanomolar Ki value. [PMID 38285527]
• A review and case report discuss Melanotan II as a non-selective melanocortin-receptor agonist and describe the literature context in which thrombotic pharmacological influence and possible direct toxic effect on renal parenchyma were considered in a proposed mechanism for renal injury. [PMID 31953620]
• A preformulation study measured dissociation constants (via potentiometric titration and UV spectrophotometry), pKa values (histidine and arginine), and apparent partition coefficient parameters at multiple pH values; it reported an observed bioavailability of 4.6% in the rat and suggested that the compound may be a suitable candidate for oral delivery based on these data. [PMID 7983590]