Allostery at opioid receptors: modulation with small molecule ligands

Livingston, Kathryn E.; Traynor, John R.

doi:10.1111/bph.13823

Cited by 66 publications

(59 citation statements)

References 86 publications

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“…One of the most pressing questions to understand more completely the mechanism of the allosteric modulators and the rational design of modulators is identification of their binding site(s) on the opioid receptors. Comparisons of two recent and independent molecular dynamics simulations suggest that the binding of BMS-986122 at m-OR (Bartuzi et al, 2016) and BMS-986187 at d-OR (Shang et al, 2016) rely on the same residues at the top of TM domains 2 and 7 (Livingston and Traynor, 2017). Indeed, the striking similarity in theoretical binding pockets for these ligands at two different opioid receptors supports our pharmacologic evidence of a conserved site.…”

Section: Discussionsupporting

confidence: 76%

“…It is also worth noting that Tyr 7.35 in k-OR, an amino acid implicated in the putative allosteric sites on d-OR and m-OR (Bartuzi et al, 2016;Shang et al, 2016), is involved in hydrogen bond formation with the orthosteric antagonist JD-Tic (Wu et al, 2012), which could indicate that JD-Tic is bitopic and reaches into the allosteric site of k-OR. This residue 7.35, as a Trp or Tyr, is crucial for the binding and function of allosteric modulators and agonistmediated conformational changes at a number of GPCRs (reviewed in Livingston and Traynor, 2017), including M1 (Abdul-Ridha et al, 2014), M2 (Jäger et al, 2007;Haga et al, 2012;Dror et al, 2013), M4 receptors (Thal et al, 2016), and b2AR and M2R (DeVree et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors

et al. 2017

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Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the -opioid receptor (-OR). BMS-986187 is a structurally distinct PAM for the -opioid receptor (-OR) that has been reported to exhibit 100-fold selectivity in promoting -OR over-OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the -OR and at the-opioid receptor (-OR), but it is ineffective at the nociceptin receptor. The affinity of BMS-986187 for -ORs and-ORs is approximately 20- to 30-fold higher than for -ORs, determined using an allosteric ternary complex model. Moreover, we provide evidence, using a silent allosteric modulator as an allosteric antagonist, that BMS-986187 and BMS-986122 bind to a similar region on all three traditional opioid receptor types (-OR, -OR, and-OR). In contrast to the dogma surrounding allosteric modulators, the results indicate a possible conserved allosteric binding site across the opioid receptor family that can accommodate structurally diverse molecules. These findings have implications for the development of selective allosteric modulators.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors

et al. 2017

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“…Moreover, this approach has the advantage that, unlike enkephalinase inhibitors which globally increase enkephalin levels, the spatial and temporal release of the peptides would be retained and so RGS inhibitors will be effective only in those areas where the peptides are released in response to noxious stimuli, but not in areas responsible other actions of the peptides. A similar concept has recently been discussed with regard to positive allosteric modulators of MOR (Burford et al, 2015;Livingston and Traynor, 2018). Thirdly, there is evidence that the beneficial analgesic action of MOR agonists (and the endogenous opioid peptides) is due to signaling downstream of G-proteins, whereas the unwanted effects of respiratory depression and constipation may be mediated via the β-arrestin pathway (Raehal et al, 2011;Violin et al, 2014;Manglik et al, 2016;Schmid et al, 2017).…”

Section: Rationale For Rgs Proteins As Potential Targets For Pain Manmentioning

confidence: 79%

Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

Senese

Kandasamy

Kochan

et al. 2020

Front. Mol. Neurosci.

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Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.

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“…Positive allosteric modulators (PAMs) of G i -coupled receptors circumvent this problem as they do not change receptor sensitivity. PAMs for the GABA B -Receptor are currently used for the treatment of drug addiction (22) while PAMs for opioid receptors are currently being developed (23).…”

Section: Novel Findingsmentioning

confidence: 99%

Repurposing established cyclic adenosine monophosphate reducing agents for the prevention and therapy of epidermal growth factor receptor inhibitor resistance in non-small cell lung cancer

Schüller

2018

Transl. Lung Cancer Res.

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Allostery at opioid receptors: modulation with small molecule ligands

Abstract: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Cited by 66 publications

References 86 publications

Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors

Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors

Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

Repurposing established cyclic adenosine monophosphate reducing agents for the prevention and therapy of epidermal growth factor receptor inhibitor resistance in non-small cell lung cancer

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