Synthesis and antinociceptive activity of some novel nonpeptide derivatives of interleukin-1 beta (193-195) sequence

The synthesis of a new series of nonpeptide derivatives of interleukin-1 beta sequence is described. Compounds have been investigated for their relative activity regarding antinociception and suppression of inflammation. Several compounds with R1(R)Lys [CH2N]-Pro structure showed better efficacy in the inflamed paw pressure test than indometacin and morphine. In terms of the relative potencies the above mentioned products (i.e. compounds 2, 4, 5, 6; ED50 values of 0.002, 0.0035, 0.0032, 0.0074 mg/kg i.p. respectively) were 10-100 times more potent than indometacin and morphine (ED50 values of 0.22 and 0.75 mg/kg). Compounds 1-14 were not able to inhibit binding of labeled interleukin-1 beta to EL 4-6.1 murine cells, since they had no affinity for interleukin-1 beta receptors. The antinociceptive activity elicited by compound 4 in the rat inflamed paw pressure test was inhibited by naloxone, but the compound was inactive in the mouse hot plate and rat paw pressure tests. These results suggest that compound 4 exerts its antinociceptive activity through a mechanism which is based on the local release of endogenous opioids in injured tissue.