G-Protein biased opioid agonists: 3-hydroxy-: N -phenethyl-5-phenylmorphans with three-carbon chain substituents at C9

Eugene S. Gutman, Eric Bow, Fuying Li, Agnieszka Sulima, Sophia Kaska, Rachel Crowley, Thomas E. Prisinzano, Yong Sok Lee, Sergio A. Hassan, Gregory H. Imler, Jeffrey R. Deschamps, Arthur E. Jacobson, Kenner C. Rice

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10 Scopus citations

Abstract

A series of compounds have been synthesized with a variety of substituents based on a three-carbon chain at the C9-position of 3-hydroxy-N-phenethyl-5-phenylmorphan (3-(2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol). Three of these were found to be μ-opioid receptor agonists in the inhibition of forskolin-induced cAMP accumulation assay and they did not recruit β-arrestin at all in the PathHunter assay and in the Tango assay. Compound 12 (3-((1S,5R,9R)-2-phenethyl-9-propyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), 13 (3-((1S,5R,9R)-9-((E)-3-hydroxyprop-1-en-1-yl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), and 15a (3-((1S,5R,9R)-9-(2-hydroxypropyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol) were partial μ-agonists. Two of them had moderate efficacies (EMAXca. 65%) and one had lower efficacy, and they were ca. 5, 3, and 4 times more potent, respectively, than morphine in vitro. Computer simulations were carried out to provide a molecular basis for the high bias ratios of the C9-substituted 5-phenylmorphans toward G-protein activation.

Original languageEnglish
Pages (from-to)896-904
Number of pages9
JournalRSC Medicinal Chemistry
Volume11
Issue number8
DOIs
StatePublished - Aug 2020

Bibliographical note

Publisher Copyright:
© 2020 The Royal Society of Chemistry.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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