title: Development of functionally selective, small molecule agonists at kappa opioid receptors.
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 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.
authors.affiliation: From the Departments of Molecular Therapeutics and Neuroscience and.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lovell
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Frankowski
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Slauson
authors.forename: Angela M
authors.initials: AM
authors.lastname: Phillips
authors.forename: John M
authors.initials: JM
authors.lastname: Streicher
authors.forename: Edward
authors.initials: E
authors.lastname: Stahl
authors.forename: Cullen L
authors.initials: CL
authors.lastname: Schmid
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Franck
authors.initials: F
authors.lastname: Madoux
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D008024:Ligands; C515653:OPRK1 protein, human; D015363:Quinolones; D017473:Receptors, Opioid, kappa; D014230:Triazoles; D000071557:beta-Arrestins; D019204:GTP-Binding Proteins
keywords: Arrestin; Brain; Drug Discovery; Dysphoria; ERK; G Protein-coupled Receptors (GPCR); Kappa Opioid Receptor; Opiate Opioid; Pain