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

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http://hdl.handle.net/10138/313633

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Ahonen , T J , Rinne , M , Grutschreiber , P , Mätlik , K , Airavaara , M , Schaarschmidt , D , Lang , H , Reiss , D , Xhaard , H , Gaveriaux-Ruff , C , Yli-Kauhaluoma , J & Moreira , V M 2018 , ' Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at 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

Title: Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors
Author: Ahonen, Tiina J.; Rinne, Maiju; Grutschreiber, Peter; Mätlik, Kert; Airavaara, Mikko; Schaarschmidt, Dieter; Lang, Heinrich; Reiss, David; Xhaard, Henri; Gaveriaux-Ruff, Claire; Yli-Kauhaluoma, Jari; Moreira, Vania M.
Contributor: University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Pharmaceutical Design and Discovery group
Date: 2018-05-10
Number of pages: 13
Belongs to series: European Journal of Medicinal Chemistry
ISSN: 0223-5234
URI: http://hdl.handle.net/10138/313633
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 Delta(7.8)-opioids to the corresponding 7 beta-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 7 beta-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7 beta-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest. (C) 2018 Elsevier Masson SAS. All rights reserved.
Subject: Morphine
Oxidation
Supported permanganate
Hydroxy ketone
Antagonist
Opioid receptor
HETEROGENEOUS PERMANGANATE OXIDATIONS
POTASSIUM-PERMANGANATE
SUPPORTED PERMANGANATE
BINDING-PROPERTIES
ORGANIC-COMPOUNDS
MORPHINE ANALOGS
OXIDIZING-AGENT
CODEINE
ACTIVATION
EFFICIENT
317 Pharmacy
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