Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure-activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling.
|Number of pages||9|
|Journal||ACS Chemical Neuroscience|
|State||Published - Aug 19 2015|
Bibliographical notePublisher Copyright:
© 2015 American Chemical Society.
- Functional selectivity
- G protein coupling
- MAP kinase
- biased agonism
ASJC Scopus subject areas
- Cognitive Neuroscience
- Cell Biology