Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

Neve, Jolien De; Barlow, Thomas; Tourwé, Dirk; Bihel, Frédéric; Simonin, Frédéric; Ballet, Steven

doi:10.1039/d1md00041a

Cited by 30 publications

(28 citation statements)

References 304 publications

(443 reference statements)

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“…Opioid peptides or synthetic opioid peptide derivatives are often utilized as selective opioid receptor agonists and antagonists in research. The pharmacology of these diverse ligands is reviewed elsewhere ( Rasakham and Liu-Chen, 2011 ; Gendron et al, 2016 ; De Neve et al, 2021 ). Some commonly studied opioid receptor agonists include DAMGO (MOR), DPDPE (DOR), U69,593 or U50,488 (KOR), and the endogenous opioid peptides, met-enkephalin (MetEnk), leu-enkephalin (LeuEnk) (DOR, MOR), and dynorphin (KOR).…”

Section: Introductionmentioning

confidence: 99%

Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain

Reeves

Shah

Muñoz

et al. 2022

Front. Mol. Neurosci.

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Opioids mediate their effects via opioid receptors: mu, delta, and kappa. At the neuronal level, opioid receptors are generally inhibitory, presynaptically reducing neurotransmitter release and postsynaptically hyperpolarizing neurons. However, opioid receptor-mediated regulation of neuronal function and synaptic transmission is not uniform in expression pattern and mechanism across the brain. The localization of receptors within specific cell types and neurocircuits determine the effects that endogenous and exogenous opioids have on brain function. In this review we will explore the similarities and differences in opioid receptor-mediated regulation of neurotransmission across different brain regions. We discuss how future studies can consider potential cell-type, regional, and neural pathway-specific effects of opioid receptors in order to better understand how opioid receptors modulate brain function.

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Section: Introductionmentioning

confidence: 99%

Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain

Reeves

Shah

Muñoz

et al. 2022

Front. Mol. Neurosci.

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“…In essence, the bias factor defines the extent of difference in relative agonist activity between two signaling assays (the bias factor is 10 ^ΔΔLogτ/K A(assay1−assay2) ) (Kenakin et al, 2012). The bias of a ligand is dependent upon the reference ligand and the type of assay used (De Neve et al, 2021). Bias factor calculations are no absolute values, but there are general trends.…”

Section: Discussionmentioning

confidence: 99%

“…All the same, it is approved by the Food and Drug Administration for the treatment of moderate to severe acute pain (Tan and Habib, 2021). Then, TRV734, a close analog of TRV130, is an orally bioavailable G protein-biased MOR agonist developed by Trevena and currently in phase I trials (James et al, 2020;De Neve et al, 2021). The data suggested that TRV734 was safe and well tolerated.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine 7.43 is important for mu-opioid receptor downstream signaling pathways activated by fentanyl

Tian¹,

Zhang

Wang

et al. 2022

Front. Pharmacol.

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G protein–coupled receptors can signal through both G proteins and ß-arrestin2. For the µ-opioid receptor (MOR), early experimental evidence from a single study suggested that G protein signaling mediates analgesia and sedation, whereas ß-arrestin signaling mediates respiratory depression and constipation. Then, receptor mutations were used to clarify which residues interact with ligands to selectively regulate signals in a ligand-specific manner. However, there is no systematic study on how to determine these residues and clarify the molecular mechanism of their influence on signal pathways. We have therefore used molecular docking to predict the amino acid sites that affect the binding of ligands and MOR. Then, the corresponding sites were mutated to determine the effect of the structural determinant of MOR on Gi/o protein and ß-arrestin pathways. The pharmacological and animal behavioral experiments in combination with molecular dynamics simulations were used to elucidate the molecular mechanism of key residues governing the signaling. Without affecting ligand binding to MOR, MORY7.43A attenuated the activation of both Gi/o protein and ß-arrestin signaling pathways stimulated by fentanyl, whereas it did not change these two pathways stimulated by morphine. Likewise, the activation peak time of extracellular regulated protein kinases was significantly prolonged at MORY7.43A compared with that at MORwildtype stimulated by fentanyl, but there was no difference stimulated by morphine. In addition, MORY7.43A significantly enhanced analgesia by fentanyl but not by morphine in the mice behavioral experiment. Furthermore, the molecular dynamics simulations showed that H6 moves toward the cellular membrane. H6 of the fentanyl–Y7.43A system moved outward more than that in the morphine–Y7.43A system. Y7.43 mutation disrupted hydrophobic interactions between W6.48 and Y7.43 in the fentanyl–Y7.43A system but not in the morphine–Y7.43A system. Our results have disclosed novel mechanisms of Y7.43 mutation affecting MOR signaling pathways. Y7.43 mutation reduced the activation of the Gi/o protein pathway and blocked the ß-arrestin2 recruitment, increased the H6 outward movement of MOR, and disrupted hydrophobic interactions. This may be responsible for the enhanced fentanyl analgesia. These findings are conducive to designing new drugs from the perspective of ligand and receptor binding, and Y7.43 is also expected to be a key site to structure optimization of synthesized compounds.

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“…Over the years, the concept of biased agonism has been extended to the other opioids receptors. Indeed, also DOR activation, known to produce analgesia, anxiolytic-and antidepressant-like effects, is linked to the development of some side effects such as tolerance and convulsions that seems mainly due to arrestin-mediated internalization (15,19,27). Moreover, recent evidence also demonstrates that KOR activation in β-arrestin KO mice induces a potent antinociceptive and antipruritic effects, thus suggesting that biased KOR agonists are able to provide analgesia without producing dysphoria, sedation, abuse potential, anxiety, stress, and depression that are common side effects related to the use of KOP agonist (15,28).…”

Section: Opioid Biased Agonismmentioning

confidence: 99%

“…This molecule demonstrates mixed MOR agonist and DOR/KOR antagonist activity (34). In murine models, mitragynine does not recruit β-arrestin-2 and induces a lower tolerance as well as physical dependence than MOR opioid agonists (15). It is also capable to produce a lower respiratory depression compared to codeine (35).…”

Section: Mitragynine and 7-hydroxymitragynine (7-hmg)mentioning

confidence: 99%

New pharmacological strategies for analgesic drug development: focus on biased m opioid receptor agonists

Rullo¹,

Losapio²,

Morosini³

et al. 2022

Pharm Adv

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Chronic pain affects more than 30% of people worldwide and although mortality rates are highest for other pathologies, it is one of the main sources of human suffering and disability that profoundly impacts patients' quality of life. To date, opioids still represent the reference treatment for moderate to severe chronic pain, however their use is strongly limited by a plethora of unwanted side effects including analgesic tolerance and opioid induced hyperalgesia. In the last few years, numerous efforts have been made in order to develop new analgesic drugs characterized by reduced side effects and by a safer pharmacological profile. Molecules capable of modulating different downstream pathways, known as biased agonists, are one proposed strategy for the treatment of chronic pain due to their suggested ability to discriminate between analgesic and adverse effect. In this review, we discuss the pharmacological outcomes of opioid biased ligands by bringing together cellular results and the available data from clinical trials; in particular, we focus on biased µ-opioid receptor agonists given their therapeutic relevance. Impact statementThe concept of MOR biased agonism has been used to identify new analgesic drugs. Although some criticism has been raised toward this strategy, it represents a useful step for the development of safer opioid analgesics.

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Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

Abstract: The discovery of G protein-biased ligands will impact both drug design and medicine. This review gives a comprehensive overview of biased ligands of the opioid family of receptors and their calculated bias factors.

Cited by 30 publications

References 304 publications

Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain

Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain

Tyrosine 7.43 is important for mu-opioid receptor downstream signaling pathways activated by fentanyl

New pharmacological strategies for analgesic drug development: focus on biased m opioid receptor agonists

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