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

Ahonen, Tiina J. and Rinne, Maiju and Grutschreiber, Peter and Mätlik, Kert and Airavaara, Mikko and Schaarschmidt, Dieter and Lang, Heinrich and Reiss, David and Xhaard, Henri and Gavériaux-Ruff, Claire and Yli-Kauhaluoma, Jari and Moreira, Vânia M. (2018) Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at the mu- and delta- opioid receptors. European Journal of Medicinal Chemistry, 151. pp. 495-507. ISSN 0223-5234 (https://doi.org/10.1016/j.ejmech.2018.02.074)

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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.

ORCID iDs

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 and Moreira, Vânia M. ORCID logoORCID: https://orcid.org/0000-0001-6169-5035;
CORE (COnnecting REpositories)