title: Synthesis, antinociceptive activity, and opioid receptor profiles of substituted trans-3-(decahydro- and octahydro-4a-isoquinolinyl)phenols.
abstract: 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).
authors.affiliation: Department of Medicinal Chemistry, Glaxo Group Research Ltd., Ware, Hertfordshire, United Kingdom.
authors.forename: D B
authors.initials: DB
authors.lastname: Judd
authors.forename: D S
authors.initials: DS
authors.lastname: Brown
authors.forename: J E
authors.initials: JE
authors.lastname: Lloyd
authors.forename: A B
authors.initials: AB
authors.lastname: McElroy
authors.forename: D I
authors.initials: DI
authors.lastname: Scopes
authors.forename: P J
authors.initials: PJ
authors.lastname: Birch
authors.forename: A G
authors.initials: AG
authors.lastname: Hayes
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheehan
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D011957:Receptors, Opioid / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D007546:Isoquinolines; D010636:Phenols; D011957:Receptors, Opioid