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

Opioids such as morphine are important pain-relieving drugs but also carry a risk of harmful side effects including addiction. Morphine is active in both healthy and inflamed tissue, however, decreasing the pKa biochemically-active amine group can promote selective binding more acidic conditions tissue reduce associated with opioids. Herein, we explore impact fluorination on fluoromorphine derivatives to identify which will bind selectively tissue. Theoretical values determined at M06-2X(SMD)/aug-cc-pVDZ level theory by calculating ΔGaq for deprotonation reactions.