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

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 recept...

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Autores principales:	Tanila Ben Haddou, Szabolcs Béni, Sándor Hosztafi, Davide Malfacini, Girolamo Calo, Helmut Schmidhammer, Mariana Spetea
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a73325779fbe481cbacb806a8cd04d23
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spelling	oai:doaj.org-article:a73325779fbe481cbacb806a8cd04d232021-11-18T08:16:12ZPharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.1932-620310.1371/journal.pone.0099231https://doaj.org/article/a73325779fbe481cbacb806a8cd04d232014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24919067/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Morphine 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.Tanila Ben HaddouSzabolcs BéniSándor HosztafiDavide MalfaciniGirolamo CaloHelmut SchmidhammerMariana SpeteaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e99231 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tanila Ben Haddou Szabolcs Béni Sándor Hosztafi Davide Malfacini Girolamo Calo Helmut Schmidhammer Mariana Spetea Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.
description	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.
format	article
author	Tanila Ben Haddou Szabolcs Béni Sándor Hosztafi Davide Malfacini Girolamo Calo Helmut Schmidhammer Mariana Spetea
author_facet	Tanila Ben Haddou Szabolcs Béni Sándor Hosztafi Davide Malfacini Girolamo Calo Helmut Schmidhammer Mariana Spetea
author_sort	Tanila Ben Haddou
title	Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.
title_short	Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.
title_full	Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.
title_fullStr	Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.
title_full_unstemmed	Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.
title_sort	pharmacological investigations of n-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/a73325779fbe481cbacb806a8cd04d23
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Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.

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