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. 2014 Jan;85(1):83-90.
doi: 10.1124/mol.113.089649. Epub 2013 Oct 10.

Identification of novel functionally selective κ-opioid receptor scaffolds

Kate L White  1 , Alex P Scopton, Marie-Laure Rives, Ruslan V Bikbulatov, Prabhakar R Polepally, Peter J Brown, Terrance Kenakin, Jonathan A Javitch, Jordan K Zjawiony, Bryan L Roth
Affiliations

Identification of novel functionally selective κ-opioid receptor scaffolds

Kate L White et al. Mol Pharmacol. 2014 Jan.

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.

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Figures

Fig. 1.
Fig. 1.
NCC library screening results. (A) Depiction of the parallel screening approach used. (B) Scatter plot showing the results of the screening of the NCC library in the arrestin assay. 1, Bestatin; 2, GR8969; 3, 2-(2-aminoethyl) pyridine; 4, N-cyano-N′-(1,1-dimethylpropyl)-N′′-3-pyridinylguanidine; 5, brucine; 6, doxapram; 7, diphenoxylate.
Fig. 2.
Fig. 2.
Arrestin mobilization and G protein activation dose-response curves of candidates for in vivo studies. The dose-response curves of candidate ligands for arrestin recruitment were measured via Tango (A), G protein activation (B), and the bias plot (C). These ligands all have similar potency and efficacy values for G protein signaling, yet the potency values for arrestin mobilization differ greatly. The bias plot highlights the differences in potency and efficacy values for each ligand in both G protein and arrestin pathways.
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