Probes for narcotic receptor mediated phenomena. 46. N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols – Carbocyclic relatives of f-oxide-bridged phenylmorphans

Oxide-bridged phenylmorphans were conceptualized as topologically distinct, structurally rigid ligands with 3-dimensional shapes that could not be appreciably modified on interaction with opioid receptors. An enantiomer of the N-phenethyl-substituted ortho-f isomer was found to have high affinity for the μ-receptor (Ki = 7 nM) and was about four times more potent than naloxone as an antagonist. In order to examine the effect of introduction of a small amount of flexibility into these molecules, we have replaced the rigid 5-membered oxide ring with a more flexible 6-membered carbon ring. Synthesis of the new N-phenethyl-substituted tricyclic N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols resulted in a two carbon-bridged relative of the f-isomers, the dihydrofuran ring was replaced by a cyclohexene ring. The carbocyclic compounds had much higher affinity and greater selectivity for the μ-receptor than the f-oxide-bridged phenylmorphans. They were also much more potent μ-antagonists, with activities comparable to naltrexone in the [35S]GTP-γ-S assay.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of an N-phenethyl-substituted carbocyclic tricyclic system with high affinity for μ-opioid receptors. ► Potent (Ke < 1 nM) and reasonably μ-selective (μ/κ ratio 20 to 27) opioid antagonists. ► Oxygen atoms (carbonyl and OH) on the carbon bridge of the inner ring do not improve affinity.