Cyclic Melanotropins. 5.¹ Importance of the C-Terminal Tripeptide (Lys-Pro-Val)

In previous work we reported that [Cys⁴,Cys¹⁰]α-a-MSH (II) and Ac-[Cys⁴,Cys¹⁰]α-a-MSH_{4_13}-NH₂ (III) were superpotent melanotropins.^{2, 3} Ac-[Cys⁴,Cys¹⁰]α-a-MSH_{4_10}-NH₂ (VI), which constitutes the cyclic analogue of the putative active site sequence-Met⁴-Glu⁵-His⁶-Phe⁷-Arg⁸-Trp⁹-Gly¹⁰-of α-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]-a-MSH_4-11-NH₂ (V) was less potent than α-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]α-a-MSH_{4_10}-NH₂ in the three assays studied. Ac-[Cys⁴,Cys¹⁰]α-a-MSH_{4_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]α-a-MSH and Ac-[Cys⁴,Cys¹⁰]α-a-MSH_{4_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]α-a-MSH_{4_12}-NH₂ (VII) that exhibited highly prolonged biological activity.