Analgesic dipeptide derivatives. Part 8. 3-Amino-2-hydroxy-4-[2-(o-nitrophenylthio)indol-3-yl]butanoic acid [AH(Nps)IBA]-containing dipeptide analogues of the analgesic compound H-Trp(Nps)-Lys-OMe

Abstract

A series of diastereoisomeric dipeptides, analogues of the analgesic compound H-Trp(Nps)Lys-OMe, containing 3-amino-2-hydroxy-4-(2-(o-nitrophenylthio)indol-3-yl]butanoic acid [AH(Nps)IBA) and Lys or Leu has been synthesized. These compounds were tested as aminopeptidase-M and -B (AP-M and AP-B) inhibitors and as analgesics. The AH(Nps)IBA-Leu dipeptides, independently of their stereochemistry, were poor inhibitors of AP-M and AP-B, with IC₅₀-values in the 10^–4 mol dm^–3 range, while the AH(Nps)IBA-Lys derivatives were poor AP-B inhibitors, with IC₅₀-values also in the 10^–4 mol dm^–3 range, and did not inhibit AP-M up to 10^–3. All the AH(Nps)IBA-Lys derivatives induced a significant dose-related analgesic activity at 1–5 µg per mouse, which was dependent on the stereochemistry, while no analgesia was observed with the corresponding Leu-containing analogues. There is no relationship between the antinociceptive effects and the AP-M inhibitory potencies of this series of compounds, indicating that the inhibition of enkephalin-degrading AP-M is not an important factor for the mode of action of this series of analgesic dipeptides.