Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at the mu- and delta- opioid receptors

Tiina J. Ahonen, Maiju Rinne, Peter Grutschreiber, Kert Mätlik, Mikko Airavaara, Dieter Schaarschmidt, Heinrich Lang, David Reiss, Henri Xhaard, Claire Gavériaux-Ruff, Jari Yli-Kauhaluoma, Vânia M. Moreira

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Despite extensive years of research, the direct oxidation of the 7,8-double bond of opioids has so far received little attention and knowledge about the effects of this modification on activity at the different opioid receptors is scarce. We herein report that potassium permanganate supported on iron (II) sulfate heptahydrate can be used as a convenient oxidant in the one-step, heterogeneous conversion of Δ7,8-opioids to the corresponding 7β-hydroxy-8-ketones. Details of the reaction mechanism are given and the effects of the substituent at position 6 of several opioids on the reaction outcome is discussed. The opioid hydroxy ketones prepared are antagonists at the mu- and delta-opioid receptors. Docking simulations and detailed structure-activity analysis revealed that the presence of the 7β-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7β-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest.
LanguageEnglish
Pages495-507
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume151
Early online date26 Mar 2018
DOIs
Publication statusPublished - 10 May 2018

Fingerprint

delta Opioid Receptor
mu Opioid Receptor
Ketones
Opioid Analgesics
Derivatives
ferrous sulfate
Potassium Permanganate
Opioid Receptors
Oxidants
Oxidation
Research

Keywords

  • morphine
  • oxidation
  • supported permanganate
  • hydroxy ketone
  • antagonist
  • opioid receptor

Cite this

Ahonen, Tiina J. ; Rinne, Maiju ; Grutschreiber, Peter ; Mätlik, Kert ; Airavaara, Mikko ; Schaarschmidt, Dieter ; Lang, Heinrich ; Reiss, David ; Xhaard, Henri ; Gavériaux-Ruff, Claire ; Yli-Kauhaluoma, Jari ; Moreira, Vânia M. / Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at the mu- and delta- opioid receptors. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 151. pp. 495-507.
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Ahonen, TJ, Rinne, M, Grutschreiber, P, Mätlik, K, Airavaara, M, Schaarschmidt, D, Lang, H, Reiss, D, Xhaard, H, Gavériaux-Ruff, C, Yli-Kauhaluoma, J & Moreira, VM 2018, 'Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at the mu- and delta- opioid receptors' European Journal of Medicinal Chemistry, vol. 151, pp. 495-507. https://doi.org/10.1016/j.ejmech.2018.02.074

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at the mu- and delta- opioid receptors. / Ahonen, Tiina J.; Rinne, Maiju; Grutschreiber, Peter; Mätlik, Kert; Airavaara, Mikko; Schaarschmidt, Dieter; Lang, Heinrich; Reiss, David; Xhaard, Henri; Gavériaux-Ruff, Claire; Yli-Kauhaluoma, Jari; Moreira, Vânia M.

In: European Journal of Medicinal Chemistry, Vol. 151, 10.05.2018, p. 495-507.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at the mu- and delta- opioid receptors

AU - Ahonen, Tiina J.

AU - Rinne, Maiju

AU - Grutschreiber, Peter

AU - Mätlik, Kert

AU - Airavaara, Mikko

AU - Schaarschmidt, Dieter

AU - Lang, Heinrich

AU - Reiss, David

AU - Xhaard, Henri

AU - Gavériaux-Ruff, Claire

AU - Yli-Kauhaluoma, Jari

AU - Moreira, Vânia M.

PY - 2018/5/10

Y1 - 2018/5/10

N2 - Despite extensive years of research, the direct oxidation of the 7,8-double bond of opioids has so far received little attention and knowledge about the effects of this modification on activity at the different opioid receptors is scarce. We herein report that potassium permanganate supported on iron (II) sulfate heptahydrate can be used as a convenient oxidant in the one-step, heterogeneous conversion of Δ7,8-opioids to the corresponding 7β-hydroxy-8-ketones. Details of the reaction mechanism are given and the effects of the substituent at position 6 of several opioids on the reaction outcome is discussed. The opioid hydroxy ketones prepared are antagonists at the mu- and delta-opioid receptors. Docking simulations and detailed structure-activity analysis revealed that the presence of the 7β-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7β-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest.

AB - Despite extensive years of research, the direct oxidation of the 7,8-double bond of opioids has so far received little attention and knowledge about the effects of this modification on activity at the different opioid receptors is scarce. We herein report that potassium permanganate supported on iron (II) sulfate heptahydrate can be used as a convenient oxidant in the one-step, heterogeneous conversion of Δ7,8-opioids to the corresponding 7β-hydroxy-8-ketones. Details of the reaction mechanism are given and the effects of the substituent at position 6 of several opioids on the reaction outcome is discussed. The opioid hydroxy ketones prepared are antagonists at the mu- and delta-opioid receptors. Docking simulations and detailed structure-activity analysis revealed that the presence of the 7β-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7β-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest.

KW - morphine

KW - oxidation

KW - supported permanganate

KW - hydroxy ketone

KW - antagonist

KW - opioid receptor

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M3 - Article

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SP - 495

EP - 507

JO - European Journal of Medicinal Chemistry

T2 - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

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