SUMMARYThe purpose of this investigation was to elucidate the biological significance of lysine11and of the tripeptide sequence ‐Lys‐Pro‐Val‐NH2for the biological activity of α‐melanocyte‐stimulating hormone. To this end thein vitromelanotropic activities of twenty‐four synthetic peptides related to the hormone were determined. Extension or reduction of the length of the lysine11side chain results in a marked decrease of the melanotropic potency of the respective analogue. The C‐terminal tripeptide (11‐13), the tetrapeptide (10‐13), and the pentapeptide (9‐13) were found to be hormonally active in the same order of magnitude as the central hexapeptide (5‐10). The following conclusion was drawn: α‐MSH possesses (in contrast to ACTH) two message sequences (active sites), (i) ‐Glu‐His‐Phe‐Arg‐Trp‐, and (ii) ‐Gly‐Lys‐Pro‐Val‐NH2which are capable of independently triggering the hormone receptor responsible for melanin dispersion. Thus, despite the close structural similarity of the two hormones, α‐MSH and ACTH appear to react with their respective target cell receptors by quite different chemica