Cyclic melanotropins. 5. Importance of the C-terminal tripeptide (Lys-Pro-Val).

Abstract

In previous work we reported that [Cys4,Cys10]-alpha-MSH (II) and Ac-[Cys4,Cys10]-alpha-MSH4-13-NH2 (III) were superpotent melanotropins. Ac-[Cys4,Cys10]-alpha-MSH4-10-NH2 (VI), which constitutes the cyclic analogue of the putative active site sequence -Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10- of alpha-MSH, was much less active. In the present investigation the contribution of the Lys11 and Pro12 residues of the C-terminal carboxamide tripeptide -Lys11-Pro12-Val13-NH2 to the potency of Cys4,Cys10 containing cyclic melanotropins was studied. Ac-[Cys4,Cys10]-alpha-MSH4-11-NH2 (V) was less potent than alpha-MSH in the frog and lizard skin bioassays and the mouse S-91 (Cloudman) melanoma adenylate cyclase assay but more potent than Ac-[Cys4,Cys10]-alpha-MSH4-10-NH2 in the three assays studied. Ac-[Cys4,Cys10]-alpha-MSH4-12-NH2 (IV) was considerably more potent than the cyclic 4-11 melanotropin and was, in fact, equipotent or even slightly more potent than [Cys4,Cys10]-alpha-MSH and Ac-[Cys4,Cys10]-alpha-MSH4-13-NH2 over the linear portion of the dose-response in all three bioassays. These results demonstrate that Lys11 and Pro12 but to a lesser extent Val13 of the C-terminal tripeptide sequence contributes to the potency of the cyclic melanotropins. The further substitution of a D-Phe7 for the L-Phe7 residue into the cyclic 4-12 analogue resulted in a highly potent compound Ac-[Cys4,D-Phe7,Cys10]-alpha-MSH4-12-NH2 (VII) that exhibited highly prolonged biological activity.