SYNTHESIS AND ANTINOCICEPTIVE ACTIVITY OF PEPTIDES RELATED TO INTERLEUKIN-1-BETA(193-195) LYS-PRO-THR

To obtain information about the structure-activity relationships of an algesic peptides, we modified the previously reported tripeptide, H-Ly s-Pro-Thr-OH (C). The proline part in C was replaced with various anal ogues of unconventional amino acids ((3aS, 7aS)-octahydroindole-2-carb oxylic acid (Oic), (S,S,S,)-2-azabiciclo(3.3.0)octane-3-carboxylic aci d (Aoc), D-Aoc, and (2S,4R)-hydroxyproline (Hyp)) with varying lipophi lic, steric, and conformational properties, and alternatively with Lys and Orn in the lysine part. Moreover, the threonine part was changed to various natural amino acids (Ser, Thr, Val, Leu). All the compounds were screened in vivo for their analgesic effects in mouse writhing t est. Compound 24 (H-Orn-Hyp-Val-OH), the most active compound within t he series, showed an ED(50) value of 10 mg/kg, which is comparable wit h the ED(50) values exhibited by indometacin (4.1 mg/kg) and the dipep tide H-Lys-D-Pro-OH (6.9 mg/kg), both used as reference drugs.