κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety, and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community.
Numerous observational studies performed over the past few decades have demonstrated the supreme "likability" and abuse and dependence liability/addictiveness of oxycodone, with more recent mechanistic studies illuminating biological underpinnings including markedly increased active transport across the blood-brain barrier, increased phasic dopaminergism in the ventral tegmental area, nucleus accumbens and related striatal reward centers, and possibly increased kappa opioid receptor-mediated withdrawal dysphoria.
Synthetic κ opioid receptor agonists have no abuse liability and well-documented antinociceptive effects; however, adverse effects (diuresis, dysphoria) preclude their use in the clinic.
Dynorphin peptides, derived from the prodynorphin (PDYN) precursor, bind to opioid receptors, preferentially the kappa-opioid receptor, and may mediate the aversive effects of drugs of abuse.