Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors

作者：Zhou Lei; Lovell Kimberly M; Frankowski Kevin J; Slauson Stephen R; Phillips Angela M; Streicher John M; Stahl Edward; Schmid Cullen L; Hodder Peter; Madoux Franck; Cameron Michael D; Prisinzano Thomas E; Aube Jeffrey^*; Bohn Laura M

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288(51): 36703-36716.

DOI：10.1074/jbc.M113.504381

• Arrestin
• Brain
• Drug Discovery
• ERK
• G Protein-coupled Receptors (GPCR)
• Opiate Opioid
• Pain
• Dysphoria
• Kappa Opioid Receptor

Background: Kappa opioid receptor (KOR) signaling may produce antinociception through G protein or dysphoria through arrestin pathways. Results: Two highly selective, brain penetrant agonist scaffolds bias KOR signaling toward G protein coupling and produce antinociception in mice. Conclusion: Described are first-in-class small molecule agonists that bias KOR signaling through G proteins. Significance: Functionally selective KOR agonists can now be used in vivo. %26lt;br%26gt;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 arrestin2 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 arrestin2 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 arrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit arrestin2. 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.

• 出版日期2013-12-20