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).

Binding and structure‐activity‐relation of benzo[f]isoquinoline‐ and norcodeinone‐derivatives at μ‐opioid receptors in the rat cerebral cortex

“…The substitutions at the nitrogen are also important as they alter the affinity of the compound for individual receptor subtypes; substitutions with unsaturated and rigid side chains such as an allyl and cyclopropylmethyl reduce the agonistic activity at IL-receptors while enhancing the affinity for x-receptors and 6-opioid receptors (Magnan et al, 1982). In addition, recent studies on a series of trans-isoquinolinylphenols suggest that modifications of the equivalent to ring C differentially affect the affinity of and selectivity for gand K-receptors (Judd et al, 1992). It will therefore be interesting to use the test compounds presented in this work to probe the binding site of these receptor types.…”