- The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments
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(-)-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-chlorophenethynorhydromorphone ((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 sideeffects 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.
- Adler, Martin W.,Bergman, Jack,Chadderdon, Aaron M.,Crowley, Rachel Saylor,Geller, Ellen B.,Hanna, Ramsey D.,Hassan, Sergio A.,Herdman, Christine A.,Inan, Saadet,Irvin, Thomas C.,Jacobson, Arthur E.,Kaska, Sophia,Katz, Jonathan L.,Kopajtic, Theresa A.,Lee, Yong-Sok,Paronis, Carol A.,Prisinzano, Thomas E.,Rice, Kenner C.,Traynor, John R.,Wang, Meining,Withey, Sarah L.
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supporting information
(2020/07/02)
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- Sulfate esters of morphine derivatives: Synthesis and characterization
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Sixteen 3-O- and 6-O-sulfate esters of morphine, codeine and some of their N-methyl quaternary derivatives were synthesized by means of sulfation with pyridine-SO3 complex and sulfuric acid/N,N′- dicyclohexylcarbodiimide. Complete 1H- and 13C-NMR assignments are given for each of the synthesized compounds based on one- and two-dimensional homo- and heteronuclear measurements. Comparative analysis of chiral properties by circular dichroism and optical rotatory dispersion revealed characteristic differences in the spectra due to changes in charge, polarity and intramolecular association by strong hydrogen bonds in aqueous solution. The synthesized sulfate esters are prospective peripheral analgesics lacking central side effects and are also useful as reference substances for various analytical studies involving sulfate ester metabolites.
- Váradi, András,Gergely, András,Béni, Szabolcs,Jankovics, Péter,Noszál, Béla,Hosztafi, Sándor
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experimental part
p. 65 - 72
(2012/03/09)
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- Opiate receptor binding properties of morphine-, dihydromorphine-, and codeine 6-O-sulfate ester congeners
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A series of 3-O-acyl-6-O-sulfate esters of morphine, dihydromorphine, N-methylmorphinium iodide, codeine, and dihydrocodeine were prepared and evaluated for their ability to bind to μ-, δ-, κ1-, κ2-, and κ3-opiate receptors. Several compounds exhibited good affinity for the μ-opiate receptor. Morphine-3-O-propionyl-6-O-sulfate had four times greater affinity than morphine at the μ-opiate receptor and was the most selective compound at this receptor subtype.
- Crooks, Peter A.,Kottayil, Santosh G.,Al-Ghananeem, Abeer M.,Byrn, Stephen R.,Allan Butterfield
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p. 4291 - 4295
(2008/02/03)
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