A Novel Kappa Opioid Receptor Antagonist with Prolonged Duration of Action

Abstract

The history of opioid use traces its roots back to ancient civilizations, where substanceslike the opium poppy (Papaver somniferum) were harnessed for their remarkable analgesic properties. Today, the conventional analgesic option is opioids that target the mu opioid receptor (MOR), however, they are associated with deleterious effects, such as the development of dependence and respiratory depression. However, the kappa opioid receptor (KOR) subtype, found on the surface of cells particularly in the brain and spinal cord, promotes the negative affect of chronic pain and blockade of KOR signaling would be therapeutically desirable. KOR antagonists including CYM53093 (i.e., Navacaprant, former BTRX-335140 and NMRA-140) are in advanced clinical development for the treatment of severe depression, anxiety and anhedonia but require frequent dosing for beneficial effects due to their relatively short duration of action. This poses challenges for patient adherence and increases treatment costs. Developing longer- acting formulations is crucial to enhance convenience, adherence, and cost-effectiveness in managing conditions like generalized anxiety, major depressive disorder, pain and its comorbidities. This study pharmacologically evaluated the potential of longer-acting temporal profile for novel KOR antagonist, CYM3063, in mice.