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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
Lovell, Kimberly M. Frankowski, Kevin J. Stahl, Edward L. Slauson, Stephen R. Yoo, Euna Prisinzano, Thomas E. Aubé, Jeffrey Bohn, Laura M.
Lovell, Kimberly M.
Frankowski, Kevin J.
Stahl, Edward L.
Slauson, Stephen R.
Yoo, Euna
Prisinzano, Thomas E.
Aubé, Jeffrey
Bohn, Laura M.
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Abstract
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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Date
2015-08-19
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ACS
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Keywords
Functional selectivity, MAP kinase, Biased agonism, G protein coupling, Arrestin, GPCR
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