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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Prisinzano, Thomas E. Slauson, Stephen R. Lovell, Kimberly M. Madoux, Franck Cameron, Michael D. Streicher, John M. Phillips, Angela M. Aubé, Jeffrey Schmid, Cullen L. Bohn, Laura M. Hodder, Peter Zhou, Lei Stahl, Edward Frankowski, Kevin J. |
| Description | Author Affiliation: Zhou L ( From the Departments of Molecular Therapeutics and Neuroscience and.) |
| Abstract | 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 ßarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through ßarrestin2 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 ßarrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit ßarrestin2. 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. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 51 |
| Volume Number | 288 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2013-12-20 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Receptors, Opioid, Kappa Agonists Animals Arrestins Metabolism CHO Cells Cricetinae Cricetulus Drug Discovery GTP-Binding Proteins Ligands Mice Mice, Inbred C57BL Quinolones Chemical Synthesis Pharmacology Signal Transduction Triazoles Research Support, N.I.H., Extramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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