dc.contributor.author | Wang, Meining | |
dc.contributor.author | Irvin, Thomas C. | |
dc.contributor.author | Herdman, Christine A. | |
dc.contributor.author | Hanna, Ramsey D. | |
dc.contributor.author | Hassan, Sergio A. | |
dc.contributor.author | Lee, Yong-Sok | |
dc.contributor.author | Kaska, Sophia | |
dc.contributor.author | Crowley, Rachel Saylor | |
dc.contributor.author | Prisinzano, Thomas E. | |
dc.contributor.author | Withey, Sarah L. | |
dc.contributor.author | Paronis, Carol A. | |
dc.contributor.author | Bergman, Jack | |
dc.contributor.author | Inan, Saadet | |
dc.contributor.author | Geller, Ellen B. | |
dc.contributor.author | Adler, Martin W. | |
dc.contributor.author | Kopajtic, Theresa A. | |
dc.contributor.author | Katz, Jonathan L. | |
dc.contributor.author | Chadderdon, Aaron M. | |
dc.contributor.author | Traynor, John R. | |
dc.contributor.author | Jacobson, Arthur E. | |
dc.contributor.author | Rice, Kenner C. | |
dc.date.accessioned | 2020-11-12T17:43:39Z | |
dc.date.available | 2020-11-12T17:43:39Z | |
dc.date.issued | 2020-06-06 | |
dc.identifier.citation | 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. (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/molecules25112640 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30848 | |
dc.description | This 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.sponsorship | NIDA grant P30 DA13429 | en_US |
dc.description.sponsorship | NIDA grant DA039997 | en_US |
dc.description.sponsorship | NIDA grant DA018151 | en_US |
dc.description.sponsorship | NIDA grant DA035857 | en_US |
dc.description.sponsorship | NIDA grant DA047574 | en_US |
dc.description.sponsorship | NIH Intramural Research Programs of the National Institute on Drug Abuse | en_US |
dc.description.sponsorship | National Institute of Alcohol Abuse and Alcoholism | en_US |
dc.description.sponsorship | NIH Intramural Research Programs of the National Institute on Drug Abuse | en_US |
dc.description.sponsorship | NIH Intramural Research Program through the Center for Information Technology | en_US |
dc.description.sponsorship | NIH Intramural Research Programs of the National Institute on Drug Abuse | en_US |
dc.publisher | MDPI | en_US |
dc.rights | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Opioid | en_US |
dc.subject | Bifunctional ligands | en_US |
dc.subject | (−)-N-phenethylnorhydromorphone analogs | en_US |
dc.subject | [35S]GTPgammaS assay | en_US |
dc.subject | Forskolin-induced cAMP accumulation assays | en_US |
dc.subject | β-arrestin recruitment assays | en_US |
dc.subject | MOR and DOR agonists | en_US |
dc.subject | Respiratory depression | en_US |
dc.subject | Bias factor | en_US |
dc.subject | Molecular modeling & simulation | en_US |
dc.title | The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Kaska, Sophia | |
kusw.kuauthor | Crowley, Rachel Saylor | |
kusw.kuauthor | Prisinzano, Thomas E. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.3390/molecules25112640 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-3319-078X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-6222-1197 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-0649-8052 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-3203-1966 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-4510-392X | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7321161 | en_US |
dc.rights.accessrights | openAccess | en_US |