Discovery of HighlyPotent G Protein-Biased BisamideKappa Opioid Receptor Agonists

Abstract Kappa opioid receptor (KOR) agonists are used clinically to treat chronic itch and are promising candidates for the treatment of pain and other maladies. Unfortunately, adverse effects have hampered the widespread clinical development of KOR agonists. Preferentially stimulating the G protein activation pathway over the βarrestin2 recruitment pathway has been proposed as a method to minimize adverse effects while maintaining antipruritic and antinociceptive properties. Through a structure–activity relationship (SAR) study of a bisamide-containing lead series, we have generated KOR agonists with subnanomolar potency in G protein signaling and several with bias for G protein activation over βarrestin2 recruitment. A representative member of the series is brain-penetrant and detectable in mouse brain and plasma 60 min post-injection. Based on these in vitro and in vivo results, the SAR explored herein identifies combinations of moieties that produce high-potency and high-bias analogs to further the development of KOR agonists.