The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of 'Tail Wags Dog' Experiments
Autor: | Sophia Kaska, Christine A. Herdman, Sergio A. Hassan, Thomas E. Prisinzano, Yong-Sok Lee, Sarah L. Withey, Saadet Inan, Martin W. Adler, Rachel Saylor Crowley, Meining Wang, Thomas C. Irvin, Jonathan L. Katz, Arthur E. Jacobson, Jack Bergman, Aaron M. Chadderdon, Theresa A. Kopajtic, Kenner C. Rice, John R. Traynor, Ellen B. Geller, Carol A. Paronis, Ramsey D. Hanna |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Agonist
forskolin-induced cAMP accumulation assays TheoryofComputation_COMPUTATIONBYABSTRACTDEVICES Molecular model molecular modeling & simulation Stereochemistry medicine.drug_class Pharmaceutical Science Stimulation 01 natural sciences Partial agonist Analytical Chemistry lcsh:QD241-441 03 medical and health sciences respiratory depression lcsh:Organic chemistry β-arrestin recruitment assays Opioid Receptor Binding TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY Drug Discovery medicine Moiety Physical and Theoretical Chemistry Receptor 030304 developmental biology 0303 health sciences 010405 organic chemistry Chemistry Organic Chemistry TheoryofComputation_GENERAL (−)-N-phenethylnorhydromorphone analogs 0104 chemical sciences MOR and DOR agonists Opioid Chemistry (miscellaneous) opioid Molecular Medicine bifunctional ligands [35S]GTPgammaS assay medicine.drug MathematicsofComputing_DISCRETEMATHEMATICS bias factor |
Zdroj: | Molecules Volume 25 Issue 11 Molecules, Vol 25, Iss 2640, p 2640 (2020) |
ISSN: | 1420-3049 |
DOI: | 10.3390/molecules25112640 |
Popis: | (&minus )-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTP&gamma S binding, forskolin-induced cAMP accumulation assay, and MOR-mediated &beta arrestin recruitment assays). &ldquo Body&rdquo and &ldquo tail&rdquo interactions with opioid receptors (a subset of Portoghese&rsquo s message-address theory) were used for molecular modeling and simulations, where the &ldquo address&rdquo can be considered the &ldquo body&rdquo of the hydromorphone molecule and the &ldquo message&rdquo 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 &delta /&mu potency ratio of 1.2 in the ([35S]GTP&gamma S) 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. |
Databáze: | OpenAIRE |
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