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The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments
Wang, Meining Irvin, Thomas C. Herdman, Christine A. Hanna, Ramsey D. Hassan, Sergio A. Lee, Yong-Sok Kaska, Sophia Crowley, Rachel Saylor Prisinzano, Thomas E. Withey, Sarah L.
Wang, Meining
Irvin, Thomas C.
Herdman, Christine A.
Hanna, Ramsey D.
Hassan, Sergio A.
Lee, Yong-Sok
Kaska, Sophia
Crowley, Rachel Saylor
Prisinzano, Thomas E.
Withey, Sarah L.
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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.
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This work is licensed under a Creative Commons Attribution 4.0 International License.
Date
2020-06-06
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MDPI
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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
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