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Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist.

Scientific reports (2018-06-14)
Viola Spahn, Giovanna Del Vecchio, Antonio Rodriguez-Gaztelumendi, Julia Temp, Dominika Labuz, Michael Kloner, Marco Reidelbach, Halina Machelska, Marcus Weber, Christoph Stein
ABSTRACT

Novel 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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Sigma-Aldrich
Guanosine 5′-diphosphate sodium salt, Type I, ≥96% (HPLC)