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

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Nov 5

PMID 24187130

Citations 84

Authors

Lei Zhou

Kimberly M Lovell

Kevin J Frankowski

Stephen R Slauson

Angela M Phillips

John M Streicher

Edward Stahl

Cullen L Schmid

Peter Hodder

Franck Madoux

Michael D Cameron

Thomas E Prisinzano

Jeffrey Aube

Laura M Bohn

Affiliations

Soon will be listed here.

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.

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