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

TitleDevelopment of functionally selective, small molecule agonists at kappa opioid receptors.
Publication TypeJournal Article
Year of Publication2013
AuthorsZhou 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
JournalJ Biol Chem
Date Published2013 Dec 20
KeywordsAnimals, 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.

Alternate JournalJ. Biol. Chem.
PubMed ID24187130
PubMed Central IDPMC3868780
Grant ListR01 DA031927 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
John M. Streicher, PhD