The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments

Meining Wang, Thomas C. Irvin, Christine A. Herdman, Ramsey D. Hanna, Sergio A. Hassan, Yong Sok Lee, Sophia Kaska, Rachel Saylor Crowley, Thomas E. Prisinzano, Sarah L. Withey, Carol A. Paronis, Jack Bergman, Saadet Inan, Ellen B. Geller, Martin W. Adler, Theresa A. Kopajtic, Jonathan L. Katz, Aaron M. Chadderdon, John R. Traynor, Arthur E. JacobsonKenner C. Rice

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). "Body"and "tail"interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address"can be considered the "body"of the hydromorphone molecule and the "message"delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chlorophenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro- 1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer sideeffects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Original languageEnglish
Article number2640
Issue number11
StatePublished - Jun 2020

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.


  • (-)-N-phenethylnorhydromorphone analogs
  • Bias factor
  • Bifunctional ligands
  • Forskolin-induced cAMP accumulation assays
  • MOR and DOR agonists
  • Opioid
  • Respiratory depression
  • [35S]GTPgammaS assay
  • β-arrestin recruitment assays

ASJC Scopus subject areas

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


Dive into the research topics of 'The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments'. Together they form a unique fingerprint.

Cite this