Analgesic dipeptide derivatives. 7. 3,7-Diamino-2-hydroxyheptanoic acid (DAHHA) containing dipeptide analogues of the analgesic compound H-Lys-Trp(Nps)-OMe

J Med Chem. 1992 Mar 6;35(5):889-95. doi: 10.1021/jm00083a013.


A series of diastereomeric dipeptides, analogues of the analgesic compound H-Lys-Trp(Nps)-OMe (2), containing 3,7-diamino-2-hydroxyheptanoic acid (DAHHA) and 2-[(o-nitrophenyl)sulfenyl]tryptophan [Trp(Nps)] has been synthesized. These compounds were tested as enkephalin-degrading aminopeptidases (APs), AP-M and AP-B inhibitors, and analgesics. The inhibitory potencies and the antinociceptive effects depended on the stereochemistry of the compounds. (2S,3R)-DAHHA-L-Trp(Nps)-OMe (26d) was a highly potent and selective enkephalin-degrading APs inhibitor, with an IC50 value in the 10(-8) M range. Although this derivative was about 10(3)-fold more potent than 2 against these enzymes, their antinociceptive effects were completely similar. These results indicate that the inhibitory capacity of this series of Trp(Nps)-containing dipeptides against enkephalin-degrading enzymes is not an important factor for their antinociceptive effects.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / antagonists & inhibitors*
  • Analgesia
  • Analgesics / chemical synthesis*
  • Animals
  • Brain / enzymology
  • CD13 Antigens
  • Cell Membrane / enzymology
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology
  • Enkephalins / metabolism
  • Heptanoic Acids / chemical synthesis*
  • Heptanoic Acids / pharmacology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Rats
  • Rats, Inbred Strains
  • Stereoisomerism
  • Structure-Activity Relationship


  • Analgesics
  • Dipeptides
  • Enkephalins
  • Heptanoic Acids
  • H-lysyl-2-(2-nitrophenylsulfenyl)tryptophan methyl ester
  • 3,7-diamino-2-hydroxyheptanoic acid-2-(2-nitrophenylsulfenyl)tryptophan methyl ester
  • Aminopeptidases
  • CD13 Antigens
  • aminopeptidase B