Anti-inflammatory activity of α-MSH(11-13) analogs: Influences of alteration in stereochemistry

D-Amino acid substitutions in the anti-inflammatory/antipyretic Ac-α-MSH(11-13)-NH₂ tripeptide of Ac-α-MSH(1-13)-NH₂ were made and the altered peptides were injected in mice treated with picryl chloride. Ear swelling, measured 3 and 6 h after application of the irritant, was reduced by IP injections of Ac-α-MSH(11-13)-NH₂, in confirmation of previous observations. Ac-[D-Lys¹¹]α-MSH(11-13)-NH₂ effected similar anti-inflammatory activity but Ac-[D-Pro¹²]α-MSH(11-13)-NH₂ was inactive. Ac-[D-Val¹³]α-MSH(11-13)-NH₂ and Ac-[D-Lys¹¹,D-Val¹³]α-MSH(11-13)-NH₂ generally had greater anti-inflammatory activity than the parent tripeptide molecule; the dose-response relations exhibited the bell-shaped characteristics seen previously with MSH peptides. The results indicate that the L-Pro¹² is essential for the anti-inflammatory activity of Ac-α-MSH(11-13)-NH₂ whereas the L-Lys¹¹ is not. D-Val¹³ substitution increased anti-inflammatory activity approximately four-fold over Ac-α-MSH(11-13)-NH₂. These results provide new structure-activity relationships of the anti-inflammatory Ac-α-MSH(11-13)-NH₂ molecule. The data support the developing idea that α-MSH and its COOH-terminal fragments modulate host responses, perhaps by antagonizing the actions of cytokines.