Research paper Synthesis, biochemical, pharmacological characterization and in silico profile modelling of highly potent opioid orvinol and thevinol derivatives Edina Sz } ucs a, b, 1 ,J  anos Marton c, 1 , Zolt  an Szab  o d ,S  andor Hosztafi e , Gabriella K  ekesi f , G  abor Tuboly g ,L  aszl  oB  anki h , Gy € ongyi Horv  ath f ,P  al T. Szab  o i , Csaba T € omb € oly a , Zsuzsanna Katalin Varga a, b ,S  andor Benyhe a , Ferenc € Otv € os a, * a Institute of Biochemistry, Biological Research Center, Temesv ari krt. 62, H-6726, Szeged, Hungary b Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged, D om t er 10, H-6720, Szeged, Hungary c ABX Advanced Biochemical Compounds, Biomedizinische Forschungsreagenzien GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454, Radeberg, Germany d Royal Institute of Technology (KTH), School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Chemistry, Organic Chemistry, S-100 44, Stockholm, Sweden e Institute of Pharmaceutical Chemistry, Semmelweis Medical University, H} ogyes Endre utca 9, H-1092, Budapest, Hungary f Department of Physiology, Faculty of Medicine, University of Szeged, D om t er 10, H-6720, Szeged, Hungary g Department of Neurology, Faculty of Medicine, University of Szeged, Semmelweis u 6, H-6725, Szeged, Hungary h Department of Traumatology, Faculty of Medicine, University of Szeged, Semmelweis u 6, H-6725, Szeged, Hungary i Research Centre for Natural Sciences, MS Metabolomics Research Laboratory, H-1117, Budapest, Magyar tud osok krt. 2, Hungary article info Article history: Received 12 November 2019 Received in revised form 22 January 2020 Accepted 12 February 2020 Available online 15 February 2020 This study is dedicated to the memory of our wonderful colleague, the late professor M aria Wollemann, MD, PhD, DSc (1923- 2019) at the Institute of Biochemistry, Bio- logical Research Centre of the Hungarian Academy of Science, Szeged, Hungary. Keywords: G-protein Efficacy Binding Mu-opioid Osteoarthritis inflammation model Interaction fingerprint 6,14-Ethenomorphinan derivatives abstract Morphine and its derivatives play inevitably important role in the m-opioid receptor (MOR) targeted antinociception. A structure-activity relationship study is presented for novel and known orvinol and thevinol derivatives with varying 3-O, 6-O, 17-N and 20-alkyl substitutions starting from agonists, an- tagonists and partial agonists. In vitro competition binding experiments with [ 3 H]DAMGO showed low subnanomolar affinity to MOR. Generally, 6-O-demethylation increased the affinity toward MOR and decreased the efficacy changing the pharmacological profile in some cases. In vivo tests in osteoarthritis inflammation model showed significant antiallodynic effects of thevinol derivatives while orvinol de- rivatives did not. The pharmacological character was modelled by computational docking to both active and inactive state models of MOR. Docking energy difference for the two states separates agonists and antagonists well while partial agonists overlapped with them. An interaction pattern of the ligands, involving the interacting receptor atoms, showed more efficient separation of the pharmacological profiles. In rats, thevinol derivatives showed antiallodynic effect in vivo. The orvinol derivatives, except for 6-O-desmethyl-dihydroetorfin(2c), did not show antiallodynic effect. © 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction Pain modulation is mainly regulated through the activation of the three classical types of opioid receptors, i.e. the m-, d- and k- opioid receptors (MOR, DOR and KOR, respectively) expressed in the neurons of the central and peripheral nervous system. The opioid receptors are members of the G-protein coupled receptors * Corresponding author. Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary. E-mail address: otvos@brc.hu (F. € Otv€ os). 1 Edina Sz} ucs and J anos Marton contributed equally to this work. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech https://doi.org/10.1016/j.ejmech.2020.112145 0223-5234/© 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). European Journal of Medicinal Chemistry 191 (2020) 112145