Therapeutic Alternatives to Current Opioid Analgesics: Selectivity for Kappa over Mu Receptor in Nalfurafine Analog, RTI-4356-8

Mu opioid agonists are the primary analgesics used for the treatment of pain, but display negative side effects and have an established abuse liability. Analgesics targeting the kappa opioid receptor are predicted to lack such abuse liability, but use has been limited due to their own adverse effects. Previous research has demonstrated that arrestin- dependent G- protein signaling pathways mediate analgesia, whereas arrestin and GRK mediated activation of phospho- p38 MAPK is involved with the aversive properties of KOR analgesics. Nalfurafine is a kappa opioid in clinical trials that lacks side effects associated with kappa opioids but is only moderately selective for the kappa opioid over mu opioid receptor. The Research Triangle Institute has developed chemical analogs of Nalfurafine, expected to have improved selectivity. In the present study, one compound (RTI-4356-8), was examined for selectivity for kappa over mu receptor activity, using activation of ERK1/2 MAPK as a read out. HEK293 cells, expressing either the kappa opioid receptor or the mu opioid receptor were analyzed by western blot analysis for phosphorylation of ERK MAPK. The data obtained demonstrated that RTI-4356-8 had low efficacy for mu activation and is more selective than the original compound. This information would help in understanding the chemistry underlying differences in signaling bias and selectivity for kappa over mu opioid receptors. It would also aid in the development of better therapeutics and end the over- reliance on current opioid analgesics for the treatment of chronic pain