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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.


ABSTRACT: 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 ?-receptor (K(i) = 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 ?-receptor than the f-oxide-bridged phenylmorphans. They were also much more potent ?-antagonists, with activities comparable to naltrexone in the [(35)S]GTP-?-S assay.

SUBMITTER: Li F 

PROVIDER: S-EPMC3569853 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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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.

Li Fuying F   Deck Jason A JA   Dersch Christina M CM   Rothman Richard B RB   Deschamps Jeffrey R JR   Jacobson Arthur E AE   Rice Kenner C KC  

European journal of medicinal chemistry 20121030


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 (K(i) = 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  ...[more]

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