Molecular extension and dissection techniques are used to design a morphine derivative that promotes selective binding in inflamed tissue due to its lower pH while avoiding dangerous activation in the brain. Morphine, a benzylisoquinoline alkaloid, is a member of the opioid class of drugs and is used to treat pain associated with inflammation. While being effective analgesics, opioids carry the risk of central side effects, including addiction, respiratory depression, and sedation. Opioids are agonists that bind to the μ-opioid peptide receptor (MOR) within central and peripheral nerves and act via a G-protein coupled receptor pathway.<br/>Deprotonation of the tertiary amine induces a negative charge on the nitrogen, discouraging binding at physiological pH (pH=7.4). The addition of a fluorine atom on a carbon beta to the amine allows fluorine’s inductive effects to decrease the pKa. Decreasing the pKa of the biochemically active amine group promotes selective binding in peripheral opioid receptors within inflamed tissue (pH=6-6.5). Protonation remains possible in lower pH environments of inflamed tissue. Activation of peripheral receptors provides analgesia, and central receptors within the brain remain inactive. A cyclohexane (C) and pyridine ring (D) are removed to increase conformational flexibility when binding to the MOR and maintaining biological function.<br/>Electronic structure calculations were performed with Gaussian 16 using the Keck Computational Research Cluster at Chapman University. Theoretical pKa values are determined at the M06-2X/aug-cc-pVDZ//SMD level of theory to calculate the ΔG°(aq) values for the amine deprotonation reactions. The pKa of morphine is determined as 8.0 via computational analysis and used as a benchmark value to compare the beta-fluorinated derivatives. Beta-fluorination decreased the overall pKa values of the morphine derivatives (pKa: 6.1-7.83) relative to morphine. The beta-fluorinated derivatives have lower pKa values with respect to the C and D dissected derivatives.

Computational design of β-fluorinated morphine derivatives for pH-specific binding

ACS Spring 2022

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