G protein signaling–biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists

2021 ◽  
Vol 118 (48) ◽  
pp. e2102178118
Author(s):  
Edward L. Stahl ◽  
Cullen L. Schmid ◽  
Agnes Acevedo-Canabal ◽  
Cai Read ◽  
Travis W. Grim ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
G Protein ◽  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Mu Opioid ◽  
Biased Agonism ◽  
Gpcr Activation

The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein–biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein–signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.

scholarly journals Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias

2018 ◽  
Vol 61 (19) ◽  
pp. 8895-8907 ◽  
Author(s):  
Nicole M. Kennedy ◽  
Cullen L. Schmid ◽  
Nicolette C. Ross ◽  
Kimberly M. Lovell ◽  
Zhizhou Yue ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Mu Opioid

scholarly journals In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling

2020 ◽  
Vol 21 (11) ◽  
pp. 3999
Author(s):  
Xiao Zhang ◽  
Shaurita D. Hutchins ◽  
Bruce E. Blough ◽  
Eric J. Vallender
Keyword(s):  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Luciferase Reporter ◽  
Response Curves ◽  
Mu Opioid ◽  
Biased Agonism ◽  
Downstream Signaling ◽  
Ligand Bias

Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately be determined by in vivo functional effects. Nonhuman primates (NHPs) are the most translational model for evaluating the behavioral effects of candidate medications, but biased signaling of these drugs at NHP MOR receptors has been unstudied. The goal of the current work was to characterize MOR ligand bias in rhesus macaques, focusing on agonists that have previously been reported to show different patterns of biased agonism in rodents and humans. Downstream signaling pathways that responded to MOR activation were identified using a luciferase reporter array. Concentration-response curves for specific pathways (cAMP, NF-ĸB, MAPK/JNK) were generated using six agonists previously reported to differ in terms of signaling bias at rodent and human MORs. Using DAMGO as a reference ligand, relative cAMP, NF-ĸB and MAPK/JNK signaling by morphine, endomorphin-1, and TRV130 were found to be comparable between species. Further, the bias patterns of across ligands for NF-ĸB and MAPK/JNK were largely similar between species. There was a high degree of concordance between rhesus macaque and human MOR receptor signaling bias for all agonists tested, further demonstrating their utility for future translational behavioral studies.

scholarly journals G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons

2018 ◽  
Vol 11 (542) ◽  
pp. eaar4309 ◽  
Author(s):  
Jo-Hao Ho ◽  
Edward L. Stahl ◽  
Cullen L. Schmid ◽  
Sarah M. Scarry ◽  
Jeffrey Aubé ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Striatal Neurons ◽  
Biased Agonism

scholarly journals Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes

2020 ◽  
Author(s):  
Kevin Zheng ◽  
Jeffrey S. Smith ◽  
Anmol Warman ◽  
Issac Choi ◽  
Jaimee N. Gundry ◽  
...  
Keyword(s):  
Complex Formation ◽  
Signaling Pathway ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Surface Receptors ◽  
Biased Agonism ◽  
G Protein Coupled

AbstractG-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, signal through the proximal effectors G proteins and β-arrestins to influence nearly every biological process. Classically, the G protein and β-arrestin signaling pathways have largely been considered separable. Recently, direct interactions between Gα protein and β-arrestin have been described and suggest a distinct GPCR signaling pathway. Within these newly described Gα:β-arrestin complexes, Gαi/o, but not other Gα protein subtypes, have been appreciated to directly interact with β-arrestin, regardless of canonical GPCR Gα protein subtype coupling. However it is unclear how biased agonists differentially regulate this newly described Gαi:β-arrestin interaction, if at all. Here we report that endogenous ligands (chemokines) of the GPCR CXCR3, CXCL9, CXCL10, and CXCL11, along with two small molecule biased CXCR3 agonists, differentially promote the formation of Gαi:β-arrestin complexes. The ability of CXCR3 agonists to form Gαi:β-arrestin complexes does not correlate well with either G protein signaling or β-arrestin recruitment. Conformational biosensors demonstrate that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We find these Gαi:β-arrestin complexes can associate with CXCR3, but not with ERK. These findings further support that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of biased agonism.

scholarly journals Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

2021 ◽  
Vol 118 (16) ◽  
pp. e2000017118
Author(s):  
Ram Kandasamy ◽  
Todd M. Hillhouse ◽  
Kathryn E. Livingston ◽  
Kelsey E. Kochan ◽  
Claire Meurice ◽  
...  
Keyword(s):  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Opioid Peptides ◽  
Chinese Hamster ◽  
Mu Opioid Receptor ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
Mu Opioid

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

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