The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments
(−)-<i>N</i>-Phenethyl analogs of optically pure <i>N</i>-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [<sup>35</sup>S]GTPγS binding, forskolin-induced cAMP accumulation assay...
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MDPI AG
2020-06-01
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| author | 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. Jacobson Kenner C. Rice |
| author_facet | 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. Jacobson Kenner C. Rice |
| author_sort | Meining Wang |
| collection | DOAJ |
| description | (−)-<i>N</i>-Phenethyl analogs of optically pure <i>N</i>-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [<sup>35</sup>S]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 <i>N</i>-phenethyl moiety. One compound, <i>N</i>-<i>p</i>-chloro-phenethynorhydromorphone ((7a<i>R</i>,12b<i>S</i>)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7a<i>H</i>)-one, <b>2i</b>), 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 ([<sup>35</sup>S]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 <i>p</i>-chlorophenethyl compound <b>2i</b> was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound <b>2i</b> did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO<sub>2</sub>), respiration was depressed in squirrel monkeys. |
| first_indexed | 2024-03-10T19:19:42Z |
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| institution | Directory Open Access Journal |
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| last_indexed | 2024-03-10T19:19:42Z |
| publishDate | 2020-06-01 |
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| series | Molecules |
| spelling | doaj.art-413521e5240a47c49d66570b815acccf2023-11-20T03:02:43ZengMDPI AGMolecules1420-30492020-06-012511264010.3390/molecules25112640The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” ExperimentsMeining Wang0Thomas C. Irvin1Christine A. Herdman2Ramsey D. Hanna3Sergio A. Hassan4Yong-Sok Lee5Sophia Kaska6Rachel Saylor Crowley7Thomas E. Prisinzano8Sarah L. Withey9Carol A. Paronis10Jack Bergman11Saadet Inan12Ellen B. Geller13Martin W. Adler14Theresa A. Kopajtic15Jonathan L. Katz16Aaron M. Chadderdon17John R. Traynor18Arthur E. Jacobson19Kenner C. Rice20Department 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment of Health and Human Services, Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USADepartment of Health and Human Services, Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USADepartment of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045-7582, USADepartment of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045-7582, USADepartment of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045-7582, USABehavioral Biology Program, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USABehavioral Biology Program, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USABehavioral Biology Program, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USACenter for Substance Abuse Research, Lewis Katz School of Medicine of Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USACenter for Substance Abuse Research, Lewis Katz School of Medicine of Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USACenter for Substance Abuse Research, Lewis Katz School of Medicine of Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USADepartment 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, USADepartment 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, USADepartment of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment 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, USADepartment 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(−)-<i>N</i>-Phenethyl analogs of optically pure <i>N</i>-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [<sup>35</sup>S]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 <i>N</i>-phenethyl moiety. One compound, <i>N</i>-<i>p</i>-chloro-phenethynorhydromorphone ((7a<i>R</i>,12b<i>S</i>)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7a<i>H</i>)-one, <b>2i</b>), 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 ([<sup>35</sup>S]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 <i>p</i>-chlorophenethyl compound <b>2i</b> was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound <b>2i</b> did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO<sub>2</sub>), respiration was depressed in squirrel monkeys.https://www.mdpi.com/1420-3049/25/11/2640opioidbifunctional ligands(−)-<i>N</i>-phenethylnorhydromorphone analogs[<sup>35</sup>S]GTPgammaS assayforskolin-induced cAMP accumulation assaysβ-arrestin recruitment assays |
| spellingShingle | 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. Jacobson Kenner C. Rice The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments Molecules opioid bifunctional ligands (−)-<i>N</i>-phenethylnorhydromorphone analogs [<sup>35</sup>S]GTPgammaS assay forskolin-induced cAMP accumulation assays β-arrestin recruitment assays |
| title | The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments |
| title_full | The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments |
| title_fullStr | The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments |
| title_full_unstemmed | The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments |
| title_short | The Intriguing Effects of Substituents in the <i>N</i>-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments |
| title_sort | intriguing effects of substituents in the i n i phenethyl moiety of norhydromorphone a bifunctional opioid from a set of tail wags dog experiments |
| topic | opioid bifunctional ligands (−)-<i>N</i>-phenethylnorhydromorphone analogs [<sup>35</sup>S]GTPgammaS assay forskolin-induced cAMP accumulation assays β-arrestin recruitment assays |
| url | https://www.mdpi.com/1420-3049/25/11/2640 |
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