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

• Published in: Journal of medicinal chemistry 1992-01, Vol.35 (1), p.48-56
• Main Authors: Judd, Duncan B, Brown, Dearg S, Lloyd, Jane E, McElroy, Andrew B, Scopes, David I. C, Birch, Phillip J, Hayes, Ann G, Sheehan, Michael J
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0022-2623; 1520-4804
• 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).