Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors

Background: Kappa opioid receptor (KOR) signaling may produce antinociception through G protein or dysphoria through arrestin pathways. Results: Two highly selective, brain penetrant agonist scaffolds bias KOR signaling toward G protein coupling and produce antinociception in mice. Conclusion: Described are first-in-class small molecule agonists that bias KOR signaling through G proteins. Significance: Functionally selective KOR agonists can now be used in vivo. The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and arrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through arrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from arrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit arrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo.