Structure鈥揂ctivity Relationship Studies of Functionally Selective Kappa Opioid Receptor Agonists that Modulate ERK 1/2 Phosphorylation While Preserving G Protein Over 尾Arrestin2 Signaling Bias

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• 作者：Kimberly M. Lovell ; Kevin J. Frankowski ; Edward L. Stahl ; Stephen R. Slauson ; Euna Yoo ; Thomas E. Prisinzano ; Jeffrey Aub茅 ; Laura M. Bohn
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：August 19, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：1411-1419
• 全文大小：529K
• ISSN：1948-7193

文摘

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 尾arrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure鈥揳ctivity 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 尾arrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/尾arrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling.