Practical and High-Yield Syntheses of Dihydromorphine from Tetrahydrothebaine and Efficient Syntheses of (8<i>S</i>)-8-Bromomorphide

Przybył, A.; Flippen‐Anderson, Judith L.; Jacobson, and Arthur E.; Rice, Kenner C.

doi:10.1021/jo0206871

Cited by 8 publications

(4 citation statements)

References 18 publications

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“…(4R,4aR,7S,7aR,12bS)-7-(Benzylamino)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol ( 26 ). To a solution of hydromorphone [ 31 , 32 ] (2.28 g, 8.0 mmol) in DCE (60 mL) was added benzylamine (0.96 mL, 8.8 mmol, 1.1 equiv), acetic acid (0.91 mL, 16.0 mmol, 2 equiv), and NaBH(OAc) 3 (2.54 g, 1.2 mmol, 1.5 equiv), respectively. The mixture was stirred at room temperature for 24 h. Water (20 mL) was added to the reaction mixture, and it was basified to a pH ~8 with 28% NH 4 OH.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines

Sulima

Morgan

et al. 2022

Molecules

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In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)–hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT–hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT–hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness.

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Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines

Sulima

Morgan

et al. 2022

Molecules

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“…We studied the demethylation of compound 3 with several reactants in different reaction conditions. Treatment of compound 3 with aqueous hydrobromic acid 30 or hydrobromic acid in acetic acid, 31,32 gave no product. Reaction of compound 3 with boron tribromide 33 (4 and 6 equivalents) in methylene chloride gave the product in 50% yield.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis, in vitro anti-inflammatory activity and molecular docking studies of novel 4,5-diarylthiophene-2-carboxamide derivatives

Shanmuganathan

Parthasarathy

Venugopal³

et al. 2016

J Chem Sci

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A series of novel 4,5-diarylthiophene-2-carboxamide containing alkyl, cycloalkyl, aryl, aryl alkyl and heterocyclic alkyl moieties were synthesized, characterized and subsequently evaluated for antiinflammatory property. Among the novel compounds, the inhibition of bovine serum albumin denaturation assay revealed that the aryl and aryl alkyl derivatives of 4,5-diarylthiophene-2-carboxamide showed antiinflammatory activity comparable to the standard drug diclofenac sodium whereas alkyl and cycloalkyl amide derivatives showed less activity. Docking studies with these compounds against cyclooxygenase-2 receptor (PDB 1D: 1PXX) indicated that they exhibit specific interactions with key residues located in the site of the COX2 structure, which corroborates the hypothesis that these molecules are potential ligands of COX2. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, identified N-(4-bromophenyl)-4,5-bis(4-hydroxyphenyl)thiophene-2-carboxamide (6k) having high binding free energy of −11.67 kcal/mole (comparable with standard diclofenac sodium) and the best docking score, indicating effective binding of the compound 6k at the active site.

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“…To prepare the necessary quantity of N-norhydromophone base (S10 in Scheme S1, see Supplementary Material) we used a previously reported efficient process (hydromorphone synthesis, Scheme S1) for the conversion of (−)-tetrahydrothebaine (S1) to dihydromorphine (S3) [28]. We found that using the HCl salt of compound S3 as the reactant instead of the hydrate (product of the basic hydrolysis of S2) could dramatically increase the yield of the oxidation [29], achieving hydromorphone hydrochloride (S4) in 90% yield.…”

Section: Chemistrymentioning

confidence: 99%

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

et al. 2020

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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-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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Practical and High-Yield Syntheses of Dihydromorphine from Tetrahydrothebaine and Efficient Syntheses of (8S)-8-Bromomorphide

Cited by 8 publications

References 18 publications

Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines

Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines

Synthesis, in vitro anti-inflammatory activity and molecular docking studies of novel 4,5-diarylthiophene-2-carboxamide derivatives

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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