Structure–Activity Relationship Studies of Functionally Selective Kappa Opioid Receptor Agonists that Modulate ERK 1/2 Phosphorylation While Preserving G Protein Over βArrestin2 Signaling Bias
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Issue Date
2015-08-19Author
Lovell, Kimberly M.
Frankowski, Kevin J.
Stahl, Edward L.
Slauson, Stephen R.
Yoo, Euna
Prisinzano, Thomas E.
Aubé, Jeffrey
Bohn, Laura M.
Publisher
ACS
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
Copyright © 2015 American Chemical Society
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Show full item recordAbstract
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.
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Citation
Lovell, K. M., Frankowski, K. J., Stahl, E. L., Slauson, S. R., Yoo, E., Prisinzano, T. E., … Bohn, L. M. (2015). Structure–Activity Relationship Studies of Functionally Selective Kappa Opioid Receptor Agonists that Modulate ERK 1/2 Phosphorylation While Preserving G Protein Over βArrestin2 Signaling Bias. ACS Chemical Neuroscience, 6(8), 1411–1419. http://doi.org/10.1021/acschemneuro.5b00092
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