TY - JOUR A1 - Spahn, Viola A1 - Del Vecchio, Giovanna A1 - Labuz, Dominika A1 - Rodriguez-Gaztelumendi, Antonio A1 - Massaly, N. A1 - Temp, Julia A1 - Durmaz, Vedat A1 - Sabri, P. A1 - Reidelbach, Marco A1 - Machelska, Halina A1 - Weber, Marcus A1 - Stein, Christoph T1 - A nontoxic pain killer designed by modeling of pathological receptor conformations JF - Science Y1 - 2017 U6 - https://doi.org/10.1126/science.aai8636 VL - 355 IS - 6328 SP - 966 EP - 969 ER - TY - JOUR A1 - Spahn, Viola A1 - Del Vecchio, Giovanna A1 - Rodriguez-Gaztelumendi, Antonio A1 - Temp, Julia A1 - Labuz, Dominika A1 - Kloner, Michael A1 - Reidelbach, Marco A1 - Machelska, Halina A1 - Weber, Marcus A1 - Stein, Christoph T1 - Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist JF - Scientific Reports N2 - Novel pain killers without adverse effects are urgently needed. Y1 - 2018 VL - 8 SP - 8965 PB - Springer Nature ER - TY - JOUR A1 - Del Vecchio, Giovanna A1 - Labuz, Dominika A1 - Temp, Julia A1 - Seitz, Viola A1 - Kloner, Michael A1 - Negrete, Roger A1 - Rodriguez-Gaztelumendi, Antonio A1 - Weber, Marcus A1 - Machelska, Halina A1 - Stein, Christoph T1 - pKa of opioid ligands as a discriminating factor for side effects JF - Scientific Reports N2 - The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived μ-opioid receptor (MOR) agonists with reduced acid dissociation constants (pKa) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pKa, MOR affinity and [35S]-GTPγS binding at low and physiological pH values. In vivo, FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pKa values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand's pKa value may be used as discriminating factor to design safer analgesics. Y1 - 2019 U6 - https://doi.org/10.1038/s41598-019-55886-1 VL - 9 SP - 19344 ER - TY - JOUR A1 - Temp, Julia A1 - Labuz, Dominika A1 - Negrete, Roger A1 - Sunkara, Vikram A1 - Machelska, Halina T1 - Pain and knee damage in male and female mice in the medial meniscal transection-induced osteoarthritis JF - Osteoarthritis and Cartilage Y1 - 2019 U6 - https://doi.org/10.1016/j.joca.2019.11.003 ER -