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

Lattanzi, Roberta; Spetea, Mariana; Schüllner, Falko; Rief, Silvia; Kraßnig, Roland; Negri, Lucia; Schmidhammer, Helmut

doi:10.1021/jm040894o

Cited by 28 publications

(74 citation statements)

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“…In line with in vitro experimental data on the high μ-OR affinity ( K i = 0.97 nM), 23 the results of the docking study revealed that 1 binds to the μ-OR in a highly favorable manner with all of the predicted interaction patterns (Table 2). The polar group at position 3 of 1 is involved in a hydrogen-bonding network formed with a few water molecules that are present in the binding pocket and mediate interactions from the ligand to the receptor via H297 6.52 .…”

Section: Resultssupporting

confidence: 78%

“…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: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

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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“…In its ability to induce constipation, however, its potency was equal to that of morphine. 39 Several morphinan compounds reported by Grundt and coworkers have displayed mixed / ␦ agonist profi le of activity. For example, among a series of 3-hydroxy-4-methoxyindolomorphinans, compound 9 was found to display full or nearly full agonist activity at all 3 receptors in the [ 35 S]GTP ␥ S binding assay using Chinese hamster ovary (CHO) cells expressing the individual human opioid receptors.…”

Section: E120mentioning

confidence: 99%

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Ananthan

2006

AAPS J

126

110

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A BSTRACTOpioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid receptors. A large number of biochemical and pharmacological studies and studies using genetically modifi ed animals have provided convincing evidence regarding the existence of modulatory interactions between opioid and ␦ receptors. Several studies indicate that ␦ receptor agonists as well as ␦ receptor antagonists can provide benefi cial modulation to the pharmacological effects of agonists. For example, ␦ agonists can enhance the analgesic potency and effi cacy of agonists, and ␦ antagonists can prevent or diminish the development of tolerance and physical dependence by agonists. On the basis of these observations, the development of new opioid ligands possessing mixed agonist/ ␦ agonist profi le and mixed agonist/ ␦ antagonist profi le has emerged as a promising new approach to analgesic drug development. A brief overview of -␦ interactions and recent developments in identifi cation of ligands possessing mixed agonist/ ␦ agonist and agonist/ ␦ antagonist activities is provided in this report. K EYWORDS:Analgesics , Opioid Ligands , Mixed Mu/Delta agonists , Mixed Mu agonist/Delta antagonists , Peptides , Nonpeptides INTRODUCTIONOpioid analgesics are the standard therapeutic agents for the treatment of moderate-to-severe pain. These drugs exert their analgesic activity through their interaction with the opioid , ␦ , or receptors as agonists. The clinical usefulness of opioid agonists such as morphine, however, is limited by signifi cant side effects such as respiratory depression, constipation, development of tolerance and physical dependence, and addiction potential. One approach to limit -receptor-mediated side effects is to selectively target ␦ and opioid receptors. This approach has been explored using agonist ligands selective for ␦ and opioid receptors but has seen only limited success. The ␦ agonists generally display limited analgesic effi cacy and receptor agonists are limited to their use as peripheral analgesics owing to their psychotomimetic and dysphoric central effects. An alternative approach that is gaining considerable interest is the development of compounds that possess mixed opioid activity at the different opioid receptors. 1 , 2 Several lines of evidence indicate the existence of physical and functional interactions between the opioid receptors, particularly between the and ␦ receptors. Several biochemical and pharmacological studies using and ␦ receptor ligands gave an early indication of such interactions between the and ␦ receptors. [3][4][5][6] The and ␦ opioid receptors exist on overlapping populations of neurons in painmodulating regions of the central nervous system, and the presence of both and ␦ receptors ...

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“…Our work in the 6-ketomorphinan class of opioid analgesics has led to the design of 14-alkoxy substituted morphinan-6-ones as MOP agonists that are highly effective antinociceptive agents in various experimental models of pain [10,11]. Replacement of the hydroxyl group in position 14 of oxymorphone with a methoxy group led to 14- O -methyloxymorphone (Figure 1), which shows 9 times increased binding affinity at the MOP receptor [13] and is up to 40 times more potent in inducing an antinociceptive effect than oxymorphone in animals [14]. Furthermore, position 6 of N -methylmorphinans has been extensively targeted, and found to play a key role in ligand interaction with the MOP receptor, and also analgesic properties.…”

Section: Introductionmentioning

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. 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

Cited by 28 publications

References 21 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

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

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

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