Preparation and Opioid Activity of Analogues of the Analgesic Dipeptide 2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide

J Med Chem. 1992 Jan 24;35(2):223-33. doi: 10.1021/jm00080a005.

Abstract

A number of analogues of the recently disclosed analgesic dipeptide 2,6-dimethyl-L-tyrosyl-D-alanine-phenylpropylamide (SC-39566, 2) were prepared. These analogues contained oxymethylene, aminomethylene, ketomethylene, bismethylene, and trans double bond (including vinyl fluoride) isosteric replacements for the amide bond between the D-alanine and phenylpropylamine units in 2. These compounds were tested in opioid binding assays and in the mouse writhing assay for analgesic activity. Though not as potent as 2, the oxymethylene, and trans double bond isosteres showed analgesic activity. The aminomethylene analogues also showed binding activity in subnanomolar concentrations at the mu receptor. The amide bond between 2,6-dimethyl-L-tyrosine and D-alanine units seems to be critical for opioid activity.

MeSH terms

  • Analgesics, Opioid / chemical synthesis*
  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology
  • Animals
  • Brain / metabolism
  • Dipeptides / chemical synthesis*
  • Dipeptides / metabolism
  • Dipeptides / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Pain Measurement / methods
  • Rats
  • Receptors, Opioid / metabolism*
  • Structure-Activity Relationship

Substances

  • Analgesics, Opioid
  • Dipeptides
  • Receptors, Opioid
  • 2,6-dimethyltyrosyl-N-(3-phenylpropyl)alaninamide