Anti-inflammatory activity of alpha-MSH(11-13) analogs: influences of alteration in stereochemistry.
D-Amino acid substitutions in the anti-inflammatory/antipyretic Ac-alpha-MSH(11-13)-NH2 tripeptide of Ac-alpha-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-alpha-MSH(11-13)-NH2, in confirmation of previous observations. Ac-[D-Lys11]alpha-MSH(11-13)-NH2 effected similar anti-inflammatory activity but Ac-[D-Pro12]alpha-MSH(11-13)-NH2 was inactive. Ac-[D-Val13]alpha-MSH(11-13)-NH2 and Ac-[D-Lys11,D-Val13]alpha-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-alpha-MSH(11-13)-NH2 whereas the L-Lys11 is not. D-Val13 substitution increased anti-inflammatory activity approximately four-fold over Ac-alpha-MSH(11-13)-NH2. These results provide new structure-activity relationships of the anti-inflammatory Ac-alpha-MSH(11-13)-NH2 molecule. The data support the developing idea that alpha-MSH and its COOH-terminal fragments modulate host responses, perhaps by antagonizing the actions of cytokines.
Hiltz
M E
ME
Department of Physiology, University of Texas Southwestern Medical Center, Dallas 75235-9040.
Catania
A
A
Lipton
J M
JM
D000818:Animals; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D009074:Melanocyte-Stimulating Hormones / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D010853:Picryl Chloride / Q000633:toxicity; D051381:Rats; D013237:Stereoisomerism
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; C043156:MSH (11-13); D009074:Melanocyte-Stimulating Hormones; D010853:Picryl Chloride