Institute of Biochemistry, Biological Research Center, Temesvári krt. 62, H-6726, Szeged, Hungary; Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720, Szeged, Hungary.
ABX Advanced Biochemical Compounds, Biomedizinische Forschungsreagenzien GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454, Radeberg, Germany.
Eur J Med Chem. 2020 Apr 1;191:112145. doi: 10.1016/j.ejmech.2020.112145. Epub 2020 Feb 15.
Morphine and its derivatives play inevitably important role in the μ-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, antagonists and partial agonists. In vitro competition binding experiments with [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 derivatives 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.
吗啡及其衍生物在μ-阿片受体（MOR）靶向镇痛中起着不可避免的重要作用。本研究对新型和已知的奥啡烷和蒂巴因衍生物进行了构效关系研究，这些衍生物具有不同的 3-O、6-O、17-N 和 20-烷基取代基，起始物为激动剂、拮抗剂和部分激动剂。[H]DAMGO 的体外竞争结合实验显示，这些化合物对 MOR 具有低纳摩尔亲和力。一般来说，6-O-去甲基化增加了对 MOR 的亲和力，并降低了效力，在某些情况下改变了药理学特征。在骨关节炎炎症模型的体内试验中，发现蒂巴因衍生物具有显著的抗痛觉过敏作用，而奥啡烷衍生物则没有。通过计算对接对 MOR 的活性和非活性状态模型进行了药理学特征建模。两种状态下的对接能差很好地分离了激动剂和拮抗剂，而部分激动剂则与它们重叠。配体的相互作用模式，涉及相互作用的受体原子，显示出更有效的药理学特征分离。在大鼠中，蒂巴因衍生物在体内表现出抗痛觉过敏作用。除了 6-O-去甲基二氢埃托啡（2c）以外，奥啡烷衍生物在体内均未表现出抗痛觉过敏作用。
