Abstract
The κ-opioid receptor (KOR)-dynorphin system has been implicated in the control of affect, cognition, and motivation, and is thought to be dysregulated in mood and psychotic disorders, as well as in various phases of opioid dependence. KOR agonists exhibit analgesic effects, although the adverse effects produced by some KOR agonists, including sedation, dysphoria, and hallucinations, have limited their clinical use. Interestingly, KOR-mediated dysphoria, assessed in rodents as aversion, has recently been attributed to the activation of the p38 mitogen-activated protein kinase pathway following arrestin recruitment to the activated KOR. Therefore, KOR-selective G protein–biased agonists, which do not recruit arrestin, have been proposed to be more effective analgesics, without the adverse effects triggered by the arrestin pathway. As an initial step toward identifying novel biased KOR agonists, we applied a multifaceted screening strategy utilizing both in silico and parallel screening approaches. We identified several KOR-selective ligand scaffolds with a range of signaling bias in vitro. The arylacetamide-based scaffold includes both G protein– and β-arrestin–biased ligands, while the endogenous peptides and the diterpene scaffolds are G protein biased. Interestingly, we found scaffold screening to be more successful than library screening in identifying biased ligands. Many of the identified functionally selective ligands are potent selective KOR agonists that are reported to be active in the central nervous system. They therefore represent excellent candidates for in vivo studies aiming at determining the behavioral effects mediated by specific KOR-mediated signaling cascades.
Footnotes
- Received September 13, 2013.
- Accepted October 10, 2013.
↵1 Current affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
The work was funded by the National Institutes of Health National Institute on Drug Abuse and National Institute of Mental Health [Grants RO1DA01724, U19MH82441, K05DA022413, and R01MH54137]; a National Institute on Drug Abuse EUREKA Grant [R01DA027170]; and the National Institute of Mental Health Psychoactive Drug Screening Program. The Structural Genomics Consortium is a registered charity (No. 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada through the Ontario Genomics Institute [OGI-055], GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust [092809/Z/10/Z].
Primary laboratory of origin: Roth.
This work was previously presented as follows: White KL, Vardy E, and Roth BL (2013) Utilizing functionally selective ligands to probe specific signaling pathways of the kappa opioid receptor. Second Conference on the Therapeutic Potential of Kappa Opioids in Pain and Addiction; 2013 Apr 24–27; Cambridge, MA. Kappa Therapeutics, Boston, MA.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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