Synthesis, antinociceptive activity, and opioid receptor profiles of substituted trans-3-(decahydro- and octahydro-4a-isoquinolinyl)phenols

J Med Chem. 1992 Jan;35(1):48-56. doi: 10.1021/jm00079a005.


A series of trans-3-(6- and 7-substituted-decahydro-4a-isoquinolinyl)phenols and trans-3-(octahydro-4a-isoquinolinyl)phenols have been synthesized as potential opioid analgesics. Using a combination of in vitro and in vivo test systems, the receptor profiles of selected compounds have been assessed and in some instances distinguish between mu- and kappa-receptor agonists. In general, introduction of a 6-exocyclic methylene group into the trans-3-(decahydro-4a-isoquinolinyl)phenol system enhanced both antinociceptive activity and kappa-opioid receptor selectivity. For each series, analogues bearing an N-cyclopropylmethyl substituent exhibited greater kappa-receptor selectivity while N-methyl derivatives showed greater mu-receptor selectivity. The 7-substituted compounds (3b) were significantly less potent antinociceptive agents than their 6-substituted counterparts (3a), the octahydroisoquinoline analogues exhibiting intermediate activity. The axial 8-methyl-6-exocyclic methylene isoquinoline (20) is the most potent compound in the mouse abdominal constriction assay (ED50 = 0.05 mg/kg sc), whereas the equatorial 8-methyl isomer (16) was significantly less potent (ED50 = 3.3 mg/kg sc).

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology
  • Animals
  • Guinea Pigs
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology
  • Male
  • Mice
  • Pain / drug therapy
  • Phenols / chemical synthesis*
  • Phenols / pharmacology
  • Rabbits
  • Receptors, Opioid / drug effects*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Analgesics
  • Isoquinolines
  • Phenols
  • Receptors, Opioid