Development of biased agonists at the kappa opioid receptor.

Kappa opioid receptors (KOR) are the primary neuronal targets of the stress peptide, dynorphin, and regulation of the KOR may present a means to modulate responses to psychological stressors. Moreover, the development of therapeutics antagonizing the KOR may be useful for treating stress‐induced relapse in those suffering from substance addiction. βArrestins are key regulatory proteins of G protein‐coupled receptors (GPCR), such as the KOR. Given that there is some evidence to suggest that βarrestin‐mediated signaling may promote the negative aspects associated with dynorphin signaling, there is considerable interest in selectively dampening transduction via the KOR‐βarrestin signaling node, while potentially maintaining the G protein coupling of the receptor. Here we describe a number of newly synthesized KOR ligands that possess varying potency and efficacy profiles across multiple signaling assays. Our early efforts hold promise for biasing drug actions toward KOR‐mediated G protein coupling and ERK activation and away from inducing βarrestin recruitment in cell based assays. NIH/NIDA grant: 1R01DA031927–01