A MOR Antagonist with High Potency and Antagonist Efficacy among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-hydroxy)phenylmorphans

Dana R. Chambers, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Arthur E. Jacobson, Kenner C. Rice

Research output: Contribution to journalArticlepeer-review


The 5-(3-hydroxy)phenylmorphan structural class of compounds are unlike the classical morphinans, 4,5-epoxymorphinans, and 6,7-benzomorphans, in that they have an equatorially oriented aromatic ring rather than the axial orientation of that ring found in the classical opioids. This modified and simplified opioid-like structure has been shown to retain antinociceptive activity, depending on its stereochemistry and substituents, and some of them have been found to be much more potent than morphine. A simple C9-hydroxy-5-(3-hydroxy)phenylmorphan enantiomer was found to be about 500 times more potent than morphine in vivo. We have previously examined C9-alkenyl and hydroxyalkyl substituents in the N-phenethyl-5-(3-hydroxy)phenylmorphan class of compounds. Comparable C9-alkyl (methyl through butyl) substituents, with their sets of diastereomers, have not been explored. All these compounds have now been synthesized to determine the effect chain-length and stereochemistry at the C9 position in the molecule might have on their interaction with opioid receptors. We now report the synthesis and in vitro activity of 16 compounds, the C9-methyl, ethyl, propyl, and butyl diastereomers, using the inhibition of forskolin-induced cAMP accumulation assay. Several potent (sub-nanomolar and nanomolar) MOR compounds were found to be selective agonists with varying efficacy. Of greatest interest, a selective MOR antagonist was discovered; it did not display any DOR or KOR agonist activity in vitro, was three times more potent than naltrexone, and was found to antagonize the EC90 of fentanyl at MOR to a greater extent than naltrexone.

Original languageEnglish
Article number5411
Issue number14
StatePublished - Jul 2023

Bibliographical note

Funding Information:
This work was also supported in part by DA051377 (to T.E.P.) and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (T.E.P.).

Funding Information:
The work of D.R.C., A.S., A.E.J. and K.C.R. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. We thank John Lloyd (Mass Spectrometry Facility, NIDDK) for the mass spectral data.

Publisher Copyright:
© 2023 by the authors.


  • N-phenethyl-5-(3-hydroxy)phenylmorphan
  • inhibition of forskolin-induced cAMP accumulation assay (cAMP assay)

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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