Development of functionally selective, small molecule agonists at kappa opioid receptors.|
Year of Publication|
Zhou L, Lovell KM, Frankowski KJ, Slauson SR, Phillips AM, Streicher JM, Stahl E, Schmid CL, Hodder P, Madoux F, Cameron MD, Prisinzano TE, Aubé J, Bohn LM|
J Biol Chem|
2013 Dec 20|
Animals, Arrestins, beta-Arrestins, CHO Cells, Cricetinae, Cricetulus, Drug Discovery, GTP-Binding Proteins, Humans, Ligands, Male, Mice, Mice, Inbred C57BL, Quinolones, Receptors, Opioid, kappa, Signal Transduction, Triazoles|
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 of KOR activation 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 activate G protein coupling but weakly recruit βarrestin2. 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.
J. Biol. Chem.|
PubMed Central ID|
R01 DA031927 / DA / NIDA NIH HHS / United States|
Development of functionally selective, small molecule agonists at kappa opioid receptors.
Faculty Member Reference:
John M. Streicher, PhD