Structure-Activity Studies of Highly Potent Cyclic [formula omitted]Melanotropin Analogues

It has been proposed14 that a β turn or other chain-reversal structure involving the residues His-Phe-Arg-Trp in α-melanocyte stimulating hormone (α-MSH) contributes to the bioactive conformation of this peptide hormone. This proposal is supported by the observation that [Cys4,Cys10]-α-MSH exhibits superagonist (>10000 α-MSH) activity in the frog skin bioassay and is about 30 times more potent in the lizard skin bioassay. Studies on the possible role of a reverse turn in the biological activities of [Cys4,Cys10]-α-MSH have been extended with the synthesis of Ac-[Cys4,Cys10]-α-MSH4-10-NH2 and Ac-[Cys4,Cys10]-α-MSH4-13-NH2. The cyclic 4-10-heptapeptide was found to be less active than α-MSH in both the frog and lizard skin bioassays, but much more potent (100 times) than its linear congener. Ac-α-MSH4_10-NH2 in the frog. With the cyclic 4-13-decapeptide, superagonist potency (equipotent to the cyclic tridecapeptide) was observed on the frog skin, and the analogue was equipotent to α-MSH in the lizard skin assay. These results support the suggestion that a cyclic reverse-turn conformation in α-MSH plays a significant role in the hormone-receptor interaction. However, the reduced potency observed with Ac-[Cys4,Cys10]-α- MSH4-10-NH2 and the superagonist activity with Ac-[Cys4,Cys10]-α-MSH4-13-NH2 suggest that the C-terminal tripeptide sequence Lys-Pro-Val-NH2 (or some component thereof) in combination with a reverse turn in the cyclic moiety are both important for the superagonist activity of the latter cyclic analogue and of [Cys4,Cys10]-α-MSH.