Functionalization of the carbonyl group in position 6 of morphinan-6-ones. development of novel 6-amino and 6-guanidino substituted 14-alkoxymorphinans

Helmut Schmidhammer, Mariana Spetea, Petra Windisch, Johannes Schütz, P. Riba, M. Al-Khrasani, S. Fürst

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The well-known opioid agonists, oxycodone and oxymorphone, and the opioid antagonists, naloxone and naltrexone, are commonly used clinical agents and research tools in the opioid field. They belong to the class of morphinan-6-ones, and produce their pharmacological effects by interacting with opioid receptors, i.e. mu (MOR), delta (DOR) and kappa (KOR). The search for potent agonists and antagonists has continuously engaged the interest of pharmaceutical research, aiming for the identification of safer therapeutic agents or discovery of opioids with novel therapeutic properties and with lesser unwanted side effects. The chemically highly versatile carbonyl group in position 6 of mophinan-6-ones permits functionalization and modification leading to numerous opioid ligands. We have focused on representative examples of various derivatives and interesting approaches for the development of structurally distinct molecules with substitution at C6 (e.g. 6-methylene, 6-hydroxy, 6-amido, bifunctional ligands), as preclinically and clinically valuable opioids. In this work, the development of 6-amino and 6-guanidino substituted 14-alkoxymorphinans, including the synthesis and phar macological investigations is presented. The new approach represented by the introduction of amino and guanidino groups into position 6 of the morphinan skeleton of 14-O-methyloxymorphone, led to compounds with high efficacy, MOR affinity and selectivity, which act as potent antinociceptive agents. Altogether, as a consequence of target drug design and synthetic efforts in the field of morphinan-6-ones, we achieve a better understanding of the function of the opioid system, and such efforts may open new avenues for further investigations.

Original languageEnglish
Pages (from-to)7391-7399
Number of pages9
JournalCurrent Pharmaceutical Design
Volume19
Issue number42
DOIs
Publication statusPublished - 2013

Fingerprint

Morphinans
Opioid Analgesics
Oxymorphone
Oxycodone
Ligands
Naltrexone
Narcotic Antagonists
mu Opioid Receptor
Drug Design
Naloxone
Skeleton
Analgesics
Pharmacology
Therapeutics

Keywords

  • 14-alkoxymorphinans
  • Agonist
  • Antagonist
  • Morphinan-6-ones
  • Morphinans
  • Opioid receptors

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Functionalization of the carbonyl group in position 6 of morphinan-6-ones. development of novel 6-amino and 6-guanidino substituted 14-alkoxymorphinans. / Schmidhammer, Helmut; Spetea, Mariana; Windisch, Petra; Schütz, Johannes; Riba, P.; Al-Khrasani, M.; Fürst, S.

In: Current Pharmaceutical Design, Vol. 19, No. 42, 2013, p. 7391-7399.

Research output: Contribution to journalArticle

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