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

Zhou, Longhu; Lovell, Kimberly M.; Frankowski, Kevin J.; Slauson, Stephen R.; Phillips, Angela M; Streicher, John M.; Stahl, Edward L.; Schmid, Cullen L.; Hodder, Peter; Madoux, Franck; Cameron, Michael D.; Prisinzano, Thomas E.; Aubé, Jeffrey; Bohn, Laura M.

doi:10.1074/jbc.m113.504381

Cited by 138 publications

(214 citation statements)

References 59 publications

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“…Calculating signal transduction coefficients for ligands tested against a reference ligand can allow one to assume transduction properties of said ligands in unstudied systems (Rajagopal et al, 2010;Zhou et al, 2013). Here we employed the widely used Black-Leff operational model to directly quantify a ligand's relative agonism, or transduction coefficient (t/K A or R) (Black and Leff, 1983;Kenakin et al, 2012;van der Westhuizen et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…Employing comparative studies of ligands by in vitro assays allows the calculation of signal transduction coefficients, which can then be easily applied across model systems (Rajagopal et al, 2010(Rajagopal et al, , 2013Kenakin et al, 2012;Kenakin and Christopoulos, 2013;Zhou et al, 2013;van der Westhuizen et al, 2014). Further, applying ligand-receptor interaction modeling in conjunction with ligand-specific signal transduction data sets can lead to identification of the various structure-activity relationships necessary for the rational design of "ideal ligands" for a particular receptor system, thus eliciting the desired outcome.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin/Orphanin FQ Opioid Receptor

et al. 2015

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Comprehensive studies that consolidate selective ligands, quantitative comparisons of G protein versus arrestin-2/3 coupling, together with structure-activity relationship models for G protein-coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin/Orphanin FQ Opioid Receptor

et al. 2015

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“…Thus, agonist efficacy toward the whole cell has a quality as well as a quantity. Representations of these different qualities of efficacy can be shown on a multiaxis plot (referred to as web plots, radar plots, or spider plots); for example, ligand-specific webs of efficacy have been shown for b-adrenoceptors (Evans et al, 2010) and k-opioid receptors (Zhou et al, 2013). The questions of efficacy quality and biased signaling become relevant to the interaction of 7TMR ligands and allosteric molecules.…”

Section: Bias Induced By Negative Allosteric Molecules and Positive Amentioning

confidence: 99%

The Effective Application of Biased Signaling to New Drug Discovery

Kenakin

2015

Mol Pharmacol

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The ability of agonists to selectively activate some but not all signaling pathways linked to pleiotropically signaling receptors has opened the possibility of obtaining molecules that emphasize beneficial signals, de-emphasize harmful signals, and concomitantly deemphasize harmful signals while blocking the harmful signals produced by endogenous agonists. The detection and quantification of biased effects is straightforward, but two important factors should be considered in the evaluation of biased effects in drug discovery. The first is that efficacy, and not bias, determines whether a given agonist signal will be observed; bias only dictates the relative concentrations at which agonist signals will appear when they do appear. Therefore, a Cartesian coordinate system plotting relative efficacy (on a scale of Log relative Intrinsic Activities) as the ordinates and Log(bias) as the abscissae is proposed as a useful tool in evaluating possible biased molecules for progression in discovery programs. Second, it should be considered that the current scales quantifying bias limit this property to the allosteric vector (ligand/receptor/coupling protein complex) and that whole-cell processing of this signal can completely change measured bias from in vitro predictions.

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“…Importantly for our story, G protein-and arrestin-coupled components of the receptor ensemble are pharmacologically dissociable, such that highly efficacious activators of G protein signaling may not promote engagement of arrestins (Walters et al, 2009;Zhou et al, 2013), rendering them effectively nondesensitizing, whereas ligands displaying no efficacy for G protein coupling may yet serve as agonists for arrestinmediated signaling events (Wei et al, 2003;Azzi et al, 2003;Gesty-Palmer et al, 2006;Zimmerman et al, 2012;). This conjunction of "pluridimensional efficacy" (Galandrin and Bouvier, 2006) and ligand "bias" has set the stage for development of novel pharmaceutical agents that act in vivo as pathway-selective agonists or as mixed agonist-antagonists that promote the activation of some pathways while inhibiting the capacity of the endogenous ligand to stimulate others.…”

Section: Introductionmentioning

confidence: 99%

Fulfilling the Promise of "Biased" G Protein–Coupled Receptor Agonism

2015

Self Cite

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The fact that over 30% of current pharmaceuticals target heptahelical G protein-coupled receptors (GPCRs) attests to their tractability as drug targets. Although GPCR drug development has traditionally focused on conventional agonists and antagonists, the growing appreciation that GPCRs mediate physiologically relevant effects via both G protein and non-G protein effectors has prompted the search for ligands that can "bias" downstream signaling in favor of one or the other process. Biased ligands are novel entities with distinct signaling profiles dictated by ligand structure, and the potential prospect of biased ligands as better drugs has been pleonastically proclaimed. Indeed, preclinical proof-of-concept studies have demonstrated that both G protein and arrestin pathwayselective ligands can promote beneficial effects in vivo while simultaneously antagonizing deleterious ones. But along with opportunity comes added complexity and new challenges for drug discovery. If ligands can be biased, then ligand classification becomes assay dependent, and more nuanced screening approaches are needed to capture ligand efficacy across several dimensions of signaling. Moreover, because the signaling repertoire of biased ligands differs from that of the native agonist, unpredicted responses may arise in vivo as these unbalanced signals propagate. For any given GPCR target, establishing a framework relating in vitro efficacy to in vivo biologic response is crucial to biased drug discovery. This review discusses approaches to describing ligand efficacy in vitro, translating ligand bias into biologic response, and developing a systemslevel understanding of biased agonism in vivo, with the overall goal of overcoming current barriers to developing biased GPCR therapeutics.

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

Cited by 138 publications

References 59 publications

Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin/Orphanin FQ Opioid Receptor

Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin/Orphanin FQ Opioid Receptor

The Effective Application of Biased Signaling to New Drug Discovery

Fulfilling the Promise of "Biased" G Protein–Coupled Receptor Agonism

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