Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 20. 14-Phenylpropoxymetopon:  An Extremely Powerful Analgesic

Schütz, Johannes; Spetea, Mariana; Koch, Martin; Aceto, Mario D.; Harris, Louis S.; Coop, and Andrew; Schmidhammer, Helmut

doi:10.1021/jm030878b

Cited by 26 publications

(51 citation statements)

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“…Chemical work targeted 14-arylalkyloxy-substituted derivatives of 2b , resulting in 14-benzyloxymetopon (14-BM, 4b ) 23 and the 14-phenylpropoxy-substituted analogue (PPOM, 5 ) 32 (Table 1). These derivatives bind with very high affinity to the μ-OR, comparable to that of 2b .…”

Section: Resultsmentioning

confidence: 99%

“…The two 14-arylalkyloxy substituted morphinans 4b and 5 showed very high antinociceptive activity in mice. 23,32 Remarkable was the observation that PPOM is an extremely potent agonist in vivo, with not only considerably improved analgesic potency compared with 2b (up to 400-fold) and morphine (up to 24000-fold) (Table 1) but also greater efficacy even than etorphine (up to 25-fold), 32 a μ-OR agonist used in veterinary medicine for anesthesia.…”

Section: Resultsmentioning

confidence: 99%

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Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Noha

Schmidhammer

Spetea

2017

ACS Chem. Neurosci.

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Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure–activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3–7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Noha

Schmidhammer

Spetea

2017

ACS Chem. Neurosci.

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“…Recently, we have reported that the introduction of a 14-phenylpropoxy group gives rise to extremely potent analgesics in morphinan-6-ones having a methyl, cyclopropylmethyl, or allyl group at the morphinan nitrogen. 10,16 Thus, it became apparent that 14-arylalkoxy substitution increases analgesic potency compared to 14-alkoxymorphinans such as 14-O-methyloxymorphone (1).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

et al. 2005

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Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-one derivatives were synthesized and biologically evaluated. Compounds 6-9 and 11 displayed affinities in the subnanomolar range to mu opioid receptors which were comparable to 14-O-methyloxymorphone (1) and 14-methoxymetopon (3), and higher than oxymorphone (2). Opioid binding affinity was sensitive to the character and length of the substituent in position 14. In smooth muscle preparations they behaved as potent agonists. Antinociceptive potencies of compounds 6-11 in the hot-plate test after sc administration in mice were considerably greater than the potency of morphine. In the colonic propulsion test, the most potent analgesic compound 7 showed negligible constipating activity at the analgesic dose. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. Introduction of a 5-methyl group has no significant effect on in vitro biological activities, but resulted in decreased antinociceptive potency.

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“…The hot-plate test was performed in mice using a modified procedure [51] of the earlier described method [52]. Each mouse was exposed to the hot plate (Thermojust Apparatus, Richmond, VA) maintained at 56°C for two trials spaced 5 min apart.…”

Section: Methodsmentioning

confidence: 99%

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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Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 20. 14-Phenylpropoxymetopon: An Extremely Powerful Analgesic

Cited by 26 publications

References 26 publications

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

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

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