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dc.contributor.authorWang, Meining
dc.contributor.authorIrvin, Thomas C.
dc.contributor.authorHerdman, Christine A.
dc.contributor.authorHanna, Ramsey D.
dc.contributor.authorHassan, Sergio A.
dc.contributor.authorLee, Yong-Sok
dc.contributor.authorKaska, Sophia
dc.contributor.authorCrowley, Rachel Saylor
dc.contributor.authorPrisinzano, Thomas E.
dc.contributor.authorWithey, Sarah L.
dc.contributor.authorParonis, Carol A.
dc.contributor.authorBergman, Jack
dc.contributor.authorInan, Saadet
dc.contributor.authorGeller, Ellen B.
dc.contributor.authorAdler, Martin W.
dc.contributor.authorKopajtic, Theresa A.
dc.contributor.authorKatz, Jonathan L.
dc.contributor.authorChadderdon, Aaron M.
dc.contributor.authorTraynor, John R.
dc.contributor.authorJacobson, Arthur E.
dc.contributor.authorRice, Kenner C.
dc.date.accessioned2020-11-12T17:43:39Z
dc.date.available2020-11-12T17:43:39Z
dc.date.issued2020-06-06
dc.identifier.citationWang, 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. (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 (Basel, Switzerland), 25(11), 2640. https://doi.org/10.3390/molecules25112640en_US
dc.identifier.urihttp://hdl.handle.net/1808/30848
dc.descriptionThis work is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.description.abstract(−)-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.en_US
dc.description.sponsorshipNIDA grant P30 DA13429en_US
dc.description.sponsorshipNIDA grant DA039997en_US
dc.description.sponsorshipNIDA grant DA018151en_US
dc.description.sponsorshipNIDA grant DA035857en_US
dc.description.sponsorshipNIDA grant DA047574en_US
dc.description.sponsorshipNIH Intramural Research Programs of the National Institute on Drug Abuseen_US
dc.description.sponsorshipNational Institute of Alcohol Abuse and Alcoholismen_US
dc.description.sponsorshipNIH Intramural Research Programs of the National Institute on Drug Abuseen_US
dc.description.sponsorshipNIH Intramural Research Program through the Center for Information Technologyen_US
dc.description.sponsorshipNIH Intramural Research Programs of the National Institute on Drug Abuseen_US
dc.publisherMDPIen_US
dc.rights© 2020 by the authors. Licensee MDPI, Basel, Switzerland.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectOpioiden_US
dc.subjectBifunctional ligandsen_US
dc.subject(−)-N-phenethylnorhydromorphone analogsen_US
dc.subject[35S]GTPgammaS assayen_US
dc.subjectForskolin-induced cAMP accumulation assaysen_US
dc.subjectβ-arrestin recruitment assaysen_US
dc.subjectMOR and DOR agonistsen_US
dc.subjectRespiratory depressionen_US
dc.subjectBias factoren_US
dc.subjectMolecular modeling & simulationen_US
dc.titleThe Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experimentsen_US
dc.typeArticleen_US
kusw.kuauthorKaska, Sophia
kusw.kuauthorCrowley, Rachel Saylor
kusw.kuauthorPrisinzano, Thomas E.
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.3390/molecules25112640en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-3319-078Xen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-6222-1197en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-0649-8052en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-3203-1966en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-4510-392Xen_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC7321161en_US
dc.rights.accessrightsopenAccessen_US


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© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Except where otherwise noted, this item's license is described as: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.