Abstract
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.
Highlights
Opioids are the strongest drugs used for the treatment of pain, but serious problems have emerged due to their epidemic misuse and adverse effects
To introduce electronegative moieties and facilitate chemical synthesis, two hydrogens were replaced by two fluorine atoms at the phenyl ring in the fentanyl structure (Fig. 1)
FF6 was synthesized by a contractor (ASCA GmbH Berlin, Germany) and its pKa was experimentally measured as 7.94 ± 0.01 by another contractor (Sirius Analytical Ltd., Forest Row, UK)
Summary
Opioids are the strongest drugs used for the treatment of pain, but serious problems have emerged due to their epidemic misuse and adverse effects (reviewed in[1]). Many painful syndromes are associated with injury-induced tissue acidosis (reviewed in6) and low extracellular pH increases opioid agonist efficacy by altering the activation of opioid receptors and possibly G proteins[3,13,14,15]. We developed a novel artificial intelligence-based design of opioids lacking central or intestinal side effects by selectively targeting opioid receptors in the acidic environment of peripheral injured tissue. This approach aims at reducing a ligand’s pKa by introducing electronegative fluorine atoms in order to preclude the protonation of its tertiary amine (an essential prerequisite for opioid receptor activation) at pH 7.4 (in brain and intestinal wall)[3,15,16]. We tested the newly designed double-fluorinated compound N-{1-[2-(2,6-difluorophenyl)ethyl]piperidine-4y l}-N-phenylpropionamide (FF6), and examined whether successively decreasing an opioid ligand’s pKa values correlates with the loss of central and intestinal side effects
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