Development of functionally selective, small molecule agonists at kappa opioid receptors

Lei Zhou, Kimberly M. Lovell, Kevin J. Frankowski, Stephen R. Slauson, Angela M. Phillips, John M. Streicher, Edward Stahl, Cullen L. Schmid, Peter Hodde, Franck Madoux, Michael D. Cameron, Thomas E. Prisinzano, Jeffrey Aubé, Laura M. Bohn

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and βarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects ofKORactivation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through βarrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from βarrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activateGprotein coupling but weakly recruitβarrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo.

Original languageEnglish
Pages (from-to)36703-36716
Number of pages14
JournalJournal of Biological Chemistry
Issue number51
StatePublished - Dec 20 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Development of functionally selective, small molecule agonists at kappa opioid receptors'. Together they form a unique fingerprint.

Cite this