A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

Dana R. Chambers, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Alexander Goldberg, Bing Xie, Lei Shi, Carol A. Paronis, Jack Bergman, Nima Nassehi, Dana E. Selley, Gregory H. Imler, Arthur E. Jacobson, Kenner C. Rice

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.

Original languageEnglish
Article number6455
JournalMolecules
Volume27
Issue number19
DOIs
StatePublished - Oct 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

Keywords

  • DOR
  • KOR agonists and antagonists
  • MOR
  • N-phenethyl-2-azabicyclo [3.3.1] nonan-5-yl) phenols
  • active (6DDF) MOR crystal structures
  • diastereomeric C9-alkenyl 5-phenylmorphans
  • inactive (4DKL) MOR crystal structures
  • m-hydroxy-N-phenethyl-5-phenylmorphan
  • molecular modeling and simulation
  • respiratory depression

ASJC Scopus subject areas

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

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