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Papers of the Week

Papers: 14 Dec 2019 - 20 Dec 2019

Animal Studies, Pharmacology/Drug Development

2019 Dec 18

Sci Rep



pKa of opioid ligands as a discriminating factor for side effects.


Del Vecchio G, Labuz D, Temp J, Seitz V, Kloner M, Negrete R, Rodriguez-Gaztelumendi A, Weber M, Machelska H, Stein C
Sci Rep. 2019 Dec 18; 9(1):19344.
PMID: 31852967.


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 (pK) 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 pK, MOR affinity and [S]-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 pK values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand's pK value may be used as discriminating factor to design safer analgesics.