Derivatives of Morphine. IV.<sup>1</sup> 14-Hydroxymorphine and 14-Hydroxydihydromorphine

Weiß, Ulrich; Daum, Sol J.

doi:10.1021/jm00325a028

Cited by 17 publications

(14 citation statements)

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“…The morphine metabolites were identified by 1 H NMR spectroscopy and mass spectrometry. When possible, spectra were compared with those of reference samples (see the article by Weiss and Daum [18]).…”

Section: Resultsmentioning

confidence: 99%

Transformations of morphine alkaloids by Pseudomonas putida M10

Long

Hailes

Kirby

et al. 1995

Appl Environ Microbiol

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The oxidation of morphine by washed-cell incubations of Pseudomonas putida M10 gave rise to a large number of transformation products including hydromorphone (dihydromorphinone), 14␤-hydroxymorphine, 14␤-hydroxymorphinone, and dihydromorphine. Similarly, in incubations with oxymorphone (14␤-hydroxydihydromorphinone) as substrate, the major transformation product was identified as oxymorphol (14␤-hydroxydihydromorphine). The identities of all these biological products were confirmed by mass spectrometry and 1 H nuclear magnetic resonance spectroscopy. This is the first report describing structural evidence for the biological synthesis of 14␤-hydroxymorphine and 14␤-hydroxymorphinone. These products have applications as intermediates in the synthesis of semisynthetic opiate drugs.

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Section: Resultsmentioning

confidence: 99%

Transformations of morphine alkaloids by Pseudomonas putida M10

Long

Hailes

Kirby

et al. 1995

Appl Environ Microbiol

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“…Similarly, N -phenylpropylnormorphine ( 2 ) was synthesized from normorphine using 3-phenylpropyl bromide as alkylating agent. Sodium borohydride reduction of 14-hydroxymorphinone in ethanol yielded 14-hydroxymorphine ( 3 ) as previously described [18]. N -Phenethyl-14-hydroxynormorphine ( 4 ) was prepared in several steps from N -phenethylnorthebaine as earlier described [28].…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, it was described that N -phenethyl substitution resulted in a 6- to 10-fold higher analgesic potency compared to morphine in rodents, while N -cyclohexylethylnormorphine was only one-third as effective [17]. Another targeted site on the morphine skeleton is the C-14 position, where introduction of a hydroxyl group induces an analgesic action of moderate strength [18]. Numerous highly potent morphine-like compounds are known, one of them being oxymorphone, a MOP agonist (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…SAR studies were performed on a series comprising of four derivatives of morphine ( 1–4 ) and two derivatives of oxymorphone ( 5 and 6 ) (Figure 1). Although the synthesis of compounds 1 [26], [27] and 3 [18] has been reported about fifty years ago, and derivative 4 was prepared twenty years ago [28], there is only spare data on their biological activities, with binding affinities and selectivities at MOP, DOP and KOP receptors not yet reported. Herein, we also describe the synthesis and biological characterization of a new N-substituted derivative of morphine, N -phenylpropylnormorphine ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

et al. 2014

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Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics.

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“…Weiss & Daum (1965) reported the synthesis of 14-hydroxymorphine (V) and hydromorphinol (X). The first was similar in potency and duration of action to morphine ; the reduced derivative was about twice as potent as morphine with a prolonged duration of action in man.…”

Section: Derivatives Of Phenanthrenementioning

confidence: 99%

The toxicity of some of the newer narcotic analgesics

Lister

1966

Journal of Pharmacy and Pharmacology

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HE toxic manifestations of the newer narcotic analgesics are in many T ways similar to those of the older established agents used for the relief of pain but there are some well established quantitative and qualitative differences. A full description of the pharmacology, clinical usage and side-effect liability of the narcotic analgesics was published for the World Health Organisation between 1954 and 1957 by Braendon, Eddy, Halbach & Wolff (1954, 1955, 1956, 1957) and this review will deal mainly with drugs which have been brought on to the market or introduced for clinical trial since 1957 ; some recent information of the toxic effects of the older established drugs will also be included. A number of critical reviews dealing with the pharmacology and clinical applications have appeared since the publication of the WHO review

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Derivatives of Morphine. IV.¹ 14-Hydroxymorphine and 14-Hydroxydihydromorphine

Cited by 17 publications

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Transformations of morphine alkaloids by Pseudomonas putida M10

Transformations of morphine alkaloids by Pseudomonas putida M10

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

The toxicity of some of the newer narcotic analgesics

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Derivatives of Morphine. IV.1 14-Hydroxymorphine and 14-Hydroxydihydromorphine

Cited by 17 publications

References 0 publications

Transformations of morphine alkaloids by Pseudomonas putida M10

Transformations of morphine alkaloids by Pseudomonas putida M10

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

The toxicity of some of the newer narcotic analgesics

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Derivatives of Morphine. IV.¹ 14-Hydroxymorphine and 14-Hydroxydihydromorphine