First Clinical Experience With TRV130: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

Soergel, David G.; Subach, Ruth Ann; Sadler, Brian M.; Connell, J; Marion, Alan; Cowan, Conrad L.; Violin, Jonathan D.; Lark, Michael W.

doi:10.1002/jcph.207

Cited by 96 publications

(83 citation statements)

References 15 publications

(31 reference statements)

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“…Several novel analgesics that act as G protein biased agonists via μ-, δ- and κ-opioid receptors have been identified (15, 22, 23), and some of these compounds have advanced to clinical trials (24). Unfortunately, discovery of cannabinoid ligands that bias CB 1 R signaling has been minimal (21).…”

Section: 0 Introductionmentioning

confidence: 99%

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Ford

Franks

Tai

et al. 2017

Pharmacological Research

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The human cannabinoid subtype 1 receptor (hCB1R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB1R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB1Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB1Rs might be improved by development of G-protein biased hCB1R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB1 receptors. Our studies found that a novel IQD-derived hCB1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB1R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB1Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ9-THC. Finally, studies of a structurally similar analog PNR-4-02 show that it is also a G protein biased hCB1R agonist. It is predicted that cannabinoid agonists that bias hCB1R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically.

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Section: 0 Introductionmentioning

confidence: 99%

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Ford

Franks

Tai

et al. 2017

Pharmacological Research

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“…In particular, this compound is the only one that is currently being evaluated in human clinical trials for acute pain management. 19–21 Other opioid ligands with promising therapeutic advantages are those that display dual characteristics of μ agonism/ δ antagonism in vitro. One of these compounds is UMB 425, 22 which has recently been demonstrated to exhibit reduced tolerance liability in vivo.…”

mentioning

confidence: 99%

How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways

2016

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Substantial attention has recently been devoted to G protein-biased agonism of the μ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management. Specifically, we carried out multimicrosecond, all-atom molecular dynamics (MD) simulations of the binding of this ligand to the activated MOR crystal structure. Analysis of >50 μs of these MD simulations provides insights into the energetically preferred binding pathway of TRV-130 and its stable pose at the orthosteric binding site of MOR. Information transfer from the TRV-130 binding pocket to the intracellular region of the receptor was also analyzed, and was compared to a similar analysis carried out on the receptor bound to the classical unbiased agonist morphine. Taken together, these studies lead to a series of testable hypotheses of ligand–receptor interactions that are expected to inform the structure-based design of improved opioid analgesics.

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“…In fact, a G protein-biased MOR ligand TRV130 (made by Trevena Inc., King of Prussia, PA, USA) with little β-arrestin recruitment activity has recently been reported to show potent analgesic effects with reduced respiratory depression and constipation compared to morphine (DeWire et al ., 2013). TRV130 was delivered intravenously and has successfully completed phase I trials for safety in healthy volunteers (Soergel et al ., 2014). The first encouraging results from phase II trials were reported in a randomized and double-blinded study in patients experiencing moderate-to-severe post-operative pain after bunionectomy.…”

Section: Biased Signaling On Selected Gpcrsmentioning

confidence: 99%

Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

Bologna

Teoh

Bayoumi

et al. 2017

Biomolecules & Therapeutics

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G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.

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First Clinical Experience With TRV130: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

Cited by 96 publications

References 15 publications

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways

Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

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