Pharmacological investigations of N-substituent variation in morphine and oxymorphone: Opioid receptor binding, signaling and antinociceptive activity

Tanila Ben Haddou, S. Béni, Sándor Hosztafi, Davide Malfacini, Girolamo Calo, Helmut Schmidhammer, Mariana Spetea

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 m 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. Copyright:

Original languageEnglish
Article numbere99231
JournalPLoS One
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 11 2014

Fingerprint

Oxymorphone
Peptide Receptors
Opioid Peptides
analgesic effect
morphine
opioid peptides
narcotics
Opioid Receptors
Morphine
Morphinans
Pharmacology
Hydroxyl Radical
Opioid Analgesics
receptors
chemical derivatives
Morphine Derivatives
Therapeutic Human Experimentation
Derivatives
Molecules
Nociception

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pharmacological investigations of N-substituent variation in morphine and oxymorphone : Opioid receptor binding, signaling and antinociceptive activity. / Haddou, Tanila Ben; Béni, S.; Hosztafi, Sándor; Malfacini, Davide; Calo, Girolamo; Schmidhammer, Helmut; Spetea, Mariana.

In: PLoS One, Vol. 9, No. 6, e99231, 11.06.2014.

Research output: Contribution to journalArticle

Haddou, Tanila Ben ; Béni, S. ; Hosztafi, Sándor ; Malfacini, Davide ; Calo, Girolamo ; Schmidhammer, Helmut ; Spetea, Mariana. / Pharmacological investigations of N-substituent variation in morphine and oxymorphone : Opioid receptor binding, signaling and antinociceptive activity. In: PLoS One. 2014 ; Vol. 9, No. 6.
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