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.
Highlights
Opioid receptor agonists are the most powerful drugs to treat severe acute and cancer-related pain
Our previous in silico studies demonstrated that exchanging hydrogen by fluorine at distinct positions in the fentanyl molecule decreases its pKa value[5]
In contrast to single starting structures used previously[5], ensembles of structures derived from molecular dynamics simulations were the basis for the calculations yielding an averaged pKa value of 6.01
Summary
Opioid receptor agonists are the most powerful drugs to treat severe acute and cancer-related pain. In contrast to previous pharmacokinetic concepts (reviewed in3), we recently developed a new pharmacodynamics-based design for peripherally-acting opioids lacking central or intestinal side effects[5]. This strategy is based on computational simulations of pathological receptor conformations and the finding that the protonation state of a ligand is crucial for its activity at opioid receptors. We hypothesized that the ligand’s pKa should be reduced to values close to the acidic pH of injured tissue This was achieved by fluorination of the piperidine ring in the μ-opioid receptor (MOR) agonist fentanyl, leading to the compound (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP). The compound (±)-N-[1-(2-fluoro-2-phenylethyl)piperidine-4-yl]-N-phenyl propionamide (FF3) was synthesized by a contractor (ASCA GmbH Berlin) and tested in vitro and in vivo in the present study
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