Discovery of Highly Potent G Protein-Biased Bisamide Kappa Opioid Receptor Agonists

Kappa opioid receptor (KOR) agonists are used clinically to treat chronic itch and are promising candidates for the treatment of pain, mood disorders, and opioid use disorder. Unfortunately, adverse effects such as diuresis and sedation have hampered the widespread clinical development of KOR agonists. Preferentially activating the G protein activation pathway over the βarrestin2 recruitment pathway has been proposed as a method to minimize adverse effects while maintaining desirable effects such as antipruritic and antinociceptive properties. Through a structure–activity relationship (SAR) study of a bisamide-containing lead series, we have generated KOR agonists with sub-nanomolar potency for activating G proteins, as well as several with high bias for G protein activation over βarrestin2 recruitment. A representative member of the series is also brain-penetrant and detectable in mouse brain and plasma 60 minutes post-injection. Based on these in vitro and in vivo results, the bisamide KOR series may yield useful compounds for further development.