Compound A, a novel dual mu and kappa opioid receptor agonist that exerts potent an analgesic effect comparable to oxycodone, showed no reinforcing effect in monkeys

Abstract

Opioids (opioid mu receptor [MOR] agonists) are one of the most powerful analgesics and are widely used around the world, however, the rapid increase in the number of deaths due to drug abuse and overdose have become a major social problem. One of the causes of opioid-mediated abuse is known to be an increase of dopamine release in nucleus accumbens (NAc) via MOR activation in brain, and this effect is also known to be counteracted by opioid kappa receptor (KOR) activation expressed in NAc. We, therefore, hypothesized that a MOR/KOR dual agonist would be able to avoid the risk of abuse and psychological dependence while maintaining a strong analgesic effect. In this study, we evaluated the analgesic effects and reinforcing effect of Compound A, a novel MOR/KOR dual agonist (non-morphinan structure) that we created and compared with those of oxycodone. To investigate in vitro functional activity of compound A, cAMP assay was conducted. Hot-plate test (55°C) in rats (n = 5/dose, p.o) was performed to assess the analgesic effect. The time-course of dopamine level in NAc in rats was determined using in vivo microdialysis method (n = 3–8/dose, i.v.). Abuse liability was assessed by rat conditioned place preference (CPP) test (n = 7/dose, i.v.) and monkey intravenous self-administration study under a fixed-ratio 30 schedule of reinforcement (n = 4/dose, i.v.). In vitro profile, Compound A exhibited MOR and KOR agonism. Compound A exhibited dose-dependent analgesic effect, with a maximum response comparable to or greater than that of oxycodone. Compound A introduced less level dopamine release in rat NAc compared to oxycodone and no increase of CPP score at the analgesic dose in rats. In monkeys, Compound A did not show any reinforcing properties over a wide dose range covering the expected clinical pharmacological exposure, whereas oxycodone showed a strong reinforcing effect. MOR/KOR dual agonists may be able to overcome the risk of abuse and psychological dependence of traditional opioids while maintaining a potent analgesic effect comparable to them, which would contribute to one solution of current opioid crisis.