Synthesis and Modification of Morphine and Codeine, Leading to Diverse Libraries with Improved Pain Relief Properties

Zarin, Mona Kamelan Zargar; Dehaen, Wim; Salehi, Peyman; Asl, Amir Ata Bahmani

doi:10.3390/pharmaceutics15061779

Cited by 6 publications

(1 citation statement)

References 100 publications

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“…Its (−)enantiomer was found to be a MOR antagonist [4]. A considerable amount of effort has been expended on the synthesis of derivatives of the classical opioids [5], as well as the 6,7-benzomorphans [6][7][8][9][10][11][12], in an attempt to ameliorate their undesirable side-effects, with relatively little success [13].…”

Section: Introductionmentioning

confidence: 99%

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

Das,

Ward,

Sulima

et al. 2023

Molecules

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(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC50 = 12 nM), and was fully efficacious (%Emax = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (−)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.

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Section: Introductionmentioning

confidence: 99%

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

Das,

Ward,

Sulima

et al. 2023

Molecules

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Recent trends and therapeutic potential of phytoceutical‐based nanoparticle delivery systems in mitigating non‐small cell lung cancer

Haysom‐McDowell,

Paudel,

Yeung

et al. 2024

Molecular Oncology

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Lung cancer is the leading cause of cancer death globally, with non‐small cell lung cancer accounting for the majority (85%) of cases. Standard treatments including chemotherapy and radiotherapy present multiple adverse effects. Medicinal plants, used for centuries, are traditionally processed by methods such as boiling and oral ingestion, However, water solubility, absorption, and hepatic metabolism reduce phytoceutical bioavailability. More recently, isolated molecular compounds from these plants can be extracted with these phytoceuticals administered either individually or as an adjunct with standard therapy. Phytoceuticals have been shown to alleviate symptoms, may reduce dosage of chemotherapy and, in some cases, enhance pharmaceutical mechanisms. Research has identified many phytoceuticals' actions on cancer‐associated pathways, such as oncogenesis, the tumour microenvironment, tumour cell proliferation, metastasis, and apoptosis. The development of novel nanoparticle delivery systems such as solid lipid nanoparticles, liquid crystalline nanoparticles, and liposomes has enhanced the bioavailability and targeted delivery of pharmaceuticals and phytoceuticals. This review explores the biological pathways associated with non‐small cell lung cancer, a diverse range of phytoceuticals, the cancer pathways they act upon, and the pros and cons of several nanoparticle delivery systems.

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Characterization of Opioid Agonist Morphine Derivatives with Emphasis on Medicinal Chemistry

Malik,

Hosztafi,

Vincze

et al. 2024

ChemMedChem

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Relieving severe pains is an unmet medical need, in which opioids are of prime importance and in the focus of pharmaceutical companies. The objective of this study is to characterize the physicochemical properties, namely basicity, lipophilicity and permeability of thirty opioid ligands, which include eleven newly synthesized compounds. pH‐potentiometry and the shake‐flask method were used for the characterization of species‐specific basicity and lipophilicity. The effective permeability was determined using a brain‐specific parallel artificial membrane permeability assay. Structural modifications, namely O‐methylation in position 3, isomerization in position 6, saturation of the double bond in position 7, 14‐hydroxylation, and the substitution of N‐(β‐phenylethyl) and N‐cyclobutylmethyl side chains all have various effects on these physicochemical properties, and these are explained and compared to computationally predicted values. Computational predictions inadequately capture hydrogen bond formation with the tertiary amino group in case of 14‐hydroxylation, just as the effects of hydroxy oxidation at position 6 and N‐methyl substitution with N‐(β‐phenylethyl). The relationship between lipophilicity, permeability and potency is presented by lipophilic efficiency plots that reveal the most promising compounds. This study emphasizes the importance of experimental determination of these essential physicochemical parameters, furthermore, it can contribute to a more thorough understanding of the pharmacokinetic properties.

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Synthesis and Modification of Morphine and Codeine, Leading to Diverse Libraries with Improved Pain Relief Properties

Cited by 6 publications

References 100 publications

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

Recent trends and therapeutic potential of phytoceutical‐based nanoparticle delivery systems in mitigating non‐small cell lung cancer

Characterization of Opioid Agonist Morphine Derivatives with Emphasis on Medicinal Chemistry

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