Development of functionally selective agonists at the kappa opioid receptor (KOR)

Abstract

The G protein‐coupled, kappa opioid receptor (KOR) is a prominent target for drug discovery efforts for the treatment of pain and addiction behaviors. The therapeutic potential of KOR agonists is currently limited because KOR activation can cause dysphoria. Moreover, dynorphin, an endogenous agonist at the KOR, is a major neuropeptide involved in responding to stress. There is evidence to suggest that KOR‐mediated aversive responses result from KOR interactions with beta‐arrestin2 (βarr2). Therefore, we sought to develop KOR agonists that are functionally selective in promoting G protein coupling over βarr2 recruitment. To discern between G protein and βarr2 pathways, proximal measures of G protein coupling ([35S]‐GTPγS binding) and βarr2:KOR enzyme fragment complementation (DiscoveRx PathHunter® assay) were used. Here we describe compounds that potently activate G protein and have little potency to recruit βarr2. It is hopeful that such pharmacological tools will prove useful in defining the complex contribution of KOR signaling to the physiological stress response and may provide insights for the development of novel drugs for treating pain and drug addiction. This work was supported by NIDA grant 5 R01 DA031927–02