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.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Spahn V,Del Vecchio G,Rodriguez-Gaztelumendi A,Temp J,Labuz D,Kloner M,Reidelbach M,Machelska H,Weber M,Stein Cdoi
10.1038/s41598-018-27313-4subject
Has Abstractpub_date
2018-06-12 00:00:00pages
8965issue
1issn
2045-2322pii
10.1038/s41598-018-27313-4journal_volume
8pub_type
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