Biomedical Applications of Synthetic Melanotropins

Alpha‐melanotropin (alpha‐melanocyte stimulating hormone, alpha‐MSH) is a hormone produced by the pituitary gland of most vertebrate animals. This melanotropic peptide, Ac‐Ser‐Tyr‐Ser‐Met‐Glu‐His‐Phe‐Arg‐Trp‐Gly‐Lys‐Pro‐Val‐NH2, regulates melanin pigmentation of the skin of some mammals. Although MSH may be absent from the human pituitary gland, this peptide can stimulate pigment formation in human skin. We have synthesized several analogues of alpha‐MSH, which are superpotent, prolonged‐acting, and resistant to inactivation by serum enzymes. One such analogue, [NLe 4 , D ‐Phe 7 ]alpha‐MSH, has proven particularly useful in a number of physiological studies. In addition, some [Nle 4 , D ‐Phe 7 ]‐substituted fragment analogues of MSH are even more active than the native hormone, alpha‐MSH. For example, these analogues are 100–1,000 times more active than alpha‐MSH in stimulating S‐91 mouse melanoma tyrosinase activity in vitro. We have successfully labeled one such peptide to high specific activity; this melanotropin, [ 3 H]‐Ac‐[Nle 4 , D ‐Phe 7 ]alpha‐MSH 4–11 NH 2 , has been shown by others to bind to B16 melanoma cells. We have also conjugated several ligands (fluorescein and biotin) to [Nle 4 , D ‐Phe 7 ]alpha‐MSH. These melanotropin conjugates might prove useful for melanotropin receptor studies and for the clinical localization of metastatic melanoma. We have demonstrated that [Nle 4 , D ‐Phe 4 ]alpha‐MSH can be topically applied and transdermally delivered across the skin of mice and humans in vitro, as determined by bioassay and RIA. Initial toxicologic studies indicate that the analogue is nontoxic to mice and is not mutagenic. Studies are underway to determine whether this analogue may prove useful as a “tanning hormone” for increasing the pigmentation of light‐skinned individuals or possibly even for treating people with certain hypopigmentary disorders.