• Viola Spahn, Giovanna Del Vecchio, Antonio Rodriguez-Gaztelumendi, Julia Temp, Dominika Labuz, Michael Kloner, Marco Reidelbach, Halina Machelska, Marcus Weber, and Christoph Stein.
• Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Anesthesiology and Intensive Care Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.
• Sci Rep. 2018 Jun 12; 8 (1): 8965.

AbstractNovel pain killers without adverse effects are urgently needed. Opioids induce central and intestinal side effects such as respiratory depression, sedation, addiction, and constipation. We have recently shown that a newly designed agonist with a reduced acid dissociation constant (pKa) abolished pain by selectively activating peripheral μ-opioid receptors (MOR) in inflamed (acidic) tissues without eliciting side effects. Here, we extended this concept in that pKa reduction to 7.22 was achieved by placing a fluorine atom at the ethylidene bridge in the parental molecule fentanyl. The new compound (FF3) showed pH-sensitive MOR affinity, [35S]-GTPγS binding, and G protein dissociation by fluorescence resonance energy transfer. It produced injury-restricted analgesia in rat models of inflammatory, postoperative, abdominal, and neuropathic pain. At high dosages, FF3 induced sedation, motor disturbance, reward, constipation, and respiratory depression. These results support our hypothesis that a ligand's pKa should be close to the pH of injured tissue to obtain analgesia without side effects.

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