Novel Class of Morphinans with Acrylonitrile Incorporated Substructures as Key Intermediates for Non-Oxygen-Bridged Opioid Ligands

Greiner, Elisabeth; Schottenberger, Herwig; Wurst, Klaus; Schmidhammer, Helmut

doi:10.1021/ja015550r

Cited by 13 publications

(15 citation statements)

References 22 publications

(25 reference statements)

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“…Oxycodone and oxymorphone (Figure 1), clinically used as opioid analgesics, are two representative examples of structural variation at C-6, where a carbonyl instead of a hydroxyl group is present in position 6. By targeting the chemically highly versatile 6-keto function of morphinan-6-ones as in oxycodone, we have previously reported on a chemically innovative modification giving rise to a novel class of morphinans with acrylonitrile incorporated substructures [29,30]. The resulted acrylonitrile incorporated 4,5-oxygen bridge-opened N- methylmorphinans ( 1 – 3 , Figure 1) emerged as high affinity and potent MOP antinociceptive agents, with a pharmacological profile comparable to that of their 6-keto counterparts [30].…”

Section: Discussionmentioning

confidence: 99%

“…14-OMC was prepared according to procedures earlier described [45]. Compounds 1 – 3 were prepared according to the published procedures [29,30]. Derivatives 4 – 6 were synthesized as described [31].…”

Section: Methodsmentioning

confidence: 99%

“…Another synthetic strategy to convert the carbonyl group of morphinan-6-ones was described by the replacement of the 6-keto group with an acrylonitrile substitution to provide the N -methylmorphinans 1 – 3 (Figure 2) [29,30], without major alterations in the opioid activities in vitro and in vivo compared to their 6-keto analogues [30]. The resulted compounds exhibited high affinity at the MOP receptor, MOP selectivity and antinociceptive potencies [30].…”

Section: Introductionmentioning

confidence: 99%

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Exploring Pharmacological Activities and Signaling of Morphinans Substituted in Position 6 as Potent Agonists Interacting with the μ Opioid Receptor

et al. 2014

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BackgroundOpioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures.ResultsThis study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone.ConclusionDevelopment of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exploring Pharmacological Activities and Signaling of Morphinans Substituted in Position 6 as Potent Agonists Interacting with the μ Opioid Receptor

et al. 2014

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“…By targeting the chemically highly versatile 6-keto function of N -methylmorphinan-6-ones as in oxycodone ( 5 ), we reported on a chemically innovative modification leading to a new class of morphinans with acrylonitrile incorporated substructures [ 80 , 81 , 82 ]. An interesting strategy to include acrylonitrile substructures into morphinans is represented by the van Leusen homologation reaction [ 83 ], wherein tosylmethylisocyanid (TosMIC) reacts with carbonyl compounds to provide the corresponding nitriles with one additional carbon atom.…”

Section: Modifications In Position 6 Of 14-oxygenated- N -Methylmorphinan-6-ones: Design Synthesis and Sar Studiesmentioning

confidence: 99%

Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

Spetea

Schmidhammer

2021

Molecules

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Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.

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“…Since the first report of Knoevenagel [2], methylene active compound has been one of the most useful synthetic methods to prepare , -unsaturated systems [3][4][5][6] like alkenes with structural diversity and 3-aryl-2-heteroaryl-acrylonitriles [7][8][9][10][11][12]. The latter are known to have interesting biological properties, including antibacterial and cytotoxic agents [13], compounds with antifungal and antitumor activity [11], antitubercular activity [14], antioxidant compounds [15], tubulin inhibitors [16], and inhibitors of kinase-3 [JNK-3] [17], as well as fluorescent probes for the detection of intracellular thiols [18], DNA detection [19] and chemosensory for detecting cations [20], and others [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New (E)-2-(1H-Indole-3-ylcarbonyl)-3-heteroaryl-acrylonitriles via Microwave-Assisted Knoevenagel Condensation

Treuer

De-la-Torre

Gutiérrez

2017

Journal of Chemistry

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Given the broad spectrum of biological uses of heteroaryl-acrylonitrile derivatives, it is necessary to find simple methods to synthesize and diversify this family of compounds. We report a stereoselective synthesis of a series of new (E)-2-(1H-indole-3-ylcarbonyl)-3-heteroaryl-acrylonitriles ( a-i) obtained from 3-(cyanoacetyl)indole and heteroaryl-aldehydes under microwaveassisted Knoevenagel reaction at 300 W of potency and 100 ∘ C. The desired derivatives ( a-i) were obtained with variable yields (30-94%) and time reactions (8-90 min). All the heteroaryl-acrylonitriles were characterized by physicoanalytical techniques such IR, 1 H, 13 C NMR, and electrospray mass spectrometry.

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Novel Class of Morphinans with Acrylonitrile Incorporated Substructures as Key Intermediates for Non-Oxygen-Bridged Opioid Ligands

Cited by 13 publications

References 22 publications

Exploring Pharmacological Activities and Signaling of Morphinans Substituted in Position 6 as Potent Agonists Interacting with the μ Opioid Receptor

Exploring Pharmacological Activities and Signaling of Morphinans Substituted in Position 6 as Potent Agonists Interacting with the μ Opioid Receptor

Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

Synthesis of New (E)-2-(1H-Indole-3-ylcarbonyl)-3-heteroaryl-acrylonitriles via Microwave-Assisted Knoevenagel Condensation

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