Prolonged antinociceptive activity of pseudodipeptide analogues of Lys-Trp(Nps) and Trp(Nps)-Lys.

Peptide bond substitution in the molecules of Lys-Trp(Nps) (LTN) and Trp(Nps)-Lys (TNL) by an aminomethylene and ketomethylene bond, respectively, afforded pseudodipeptides with analgesic activity. The new compounds Lys psi(CH2NH)-Trp(Nps)-OMe (LTNAM) and Trp(Nps)psi(COCH2)(R,S)-Lys (TNLKM) induced a dose-dependent and naloxone-reversible analgesia following intracerebroventricular (ICV) administration to mice. The antinociceptive effects were longer lasting compared to those induced by the parent compounds. The pseudodipeptides protected Met-enkephalin degradation by rat striatal slices and, combined with an ineffective dose of the opioid peptide, induced analgesia. LTNAM and TNLKM were as potent as LTN to inhibit brain aminopeptidase in vitro and ex vivo. An increased resistance to proteolysis of the pseudodipeptides may explain their prolonged analgesic activity.