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J Biol Chem. 2013 Dec 20;288(51):36703-16. doi: 10.1074/jbc.M113.504381. Epub 2013 Nov 1.

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

Author information

1
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 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.

KEYWORDS:

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

PMID:
24187130
PMCID:
PMC3868780
DOI:
10.1074/jbc.M113.504381
[Indexed for MEDLINE]
Free PMC Article

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