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Article

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

1
Department of Health and Human Services, Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA
2
Department of Health and Human Services, Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA
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Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045-7582, USA
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Behavioral Biology Program, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
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Center for Substance Abuse Research, Lewis Katz School of Medicine of Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USA
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Department of Health and Human Services, Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
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Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Mariana Spetea
Molecules 2020, 25(11), 2640; https://doi.org/10.3390/molecules25112640
Received: 24 April 2020 / Revised: 2 June 2020 / Accepted: 3 June 2020 / Published: 6 June 2020
(−)-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-chloro-phenethynorhydromorphone ((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 side-effects 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. View Full-Text
Keywords: opioid; bifunctional ligands; (−)-N-phenethylnorhydromorphone analogs; [35S]GTPgammaS assay; forskolin-induced cAMP accumulation assays; β-arrestin recruitment assays; MOR and DOR agonists; respiratory depression; bias factor; molecular modeling & simulation opioid; bifunctional ligands; (−)-N-phenethylnorhydromorphone analogs; [35S]GTPgammaS assay; forskolin-induced cAMP accumulation assays; β-arrestin recruitment assays; MOR and DOR agonists; respiratory depression; bias factor; molecular modeling & simulation
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MDPI and ACS Style

Wang, M.; Irvin, T.C.; Herdman, C.A.; Hanna, R.D.; Hassan, S.A.; Lee, Y.-S.; Kaska, S.; Crowley, R.S.; Prisinzano, T.E.; Withey, S.L.; Paronis, C.A.; Bergman, J.; Inan, S.; Geller, E.B.; Adler, M.W.; Kopajtic, T.A.; Katz, J.L.; Chadderdon, A.M.; Traynor, J.R.; Jacobson, A.E.; Rice, K.C. The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments. Molecules 2020, 25, 2640. https://doi.org/10.3390/molecules25112640

AMA Style

Wang M, Irvin TC, Herdman CA, Hanna RD, Hassan SA, Lee Y-S, Kaska S, Crowley RS, Prisinzano TE, Withey SL, Paronis CA, Bergman J, Inan S, Geller EB, Adler MW, Kopajtic TA, Katz JL, Chadderdon AM, Traynor JR, Jacobson AE, Rice KC. The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments. Molecules. 2020; 25(11):2640. https://doi.org/10.3390/molecules25112640

Chicago/Turabian Style

Wang, Meining, Thomas C. Irvin, Christine A. Herdman, Ramsey D. Hanna, Sergio A. Hassan, Yong-Sok Lee, Sophia Kaska, Rachel S. 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. Jacobson, and Kenner C. Rice. 2020. "The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments" Molecules 25, no. 11: 2640. https://doi.org/10.3390/molecules25112640

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