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International Journal of Molecular... Dec 2021Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue... (Review)
Review
Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue characterized by acidic pH. The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding to the opioid receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding, and the functioning of GPCRs may involve protonation change. In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors from the perspective of the usefulness of computational studies to evaluate protonation-coupled opioid-receptor interactions.
Topics: Analgesics, Opioid; Humans; Pain; Receptors, Opioid
PubMed: 34948150
DOI: 10.3390/ijms222413353 -
Frontiers in Immunology 2020The opioid family of GPCRs consists of the classical opioid receptors, designated μ-, κ-, and δ-opioid receptors, and the orphanin-FQ receptor, and these proteins are... (Review)
Review
The opioid family of GPCRs consists of the classical opioid receptors, designated μ-, κ-, and δ-opioid receptors, and the orphanin-FQ receptor, and these proteins are expressed on both neuronal and hematopoietic cells. A number of laboratories have reported that an important degree of cross-talk can occur between the opioid receptors and the chemokine and chemokine receptor families. As a part of this, the opioid receptors are known to regulate the expression of certain chemokines and chemokine receptors, including those that possess strong pro-inflammatory activity. At the level of receptor function, it is clear that certain members of the chemokine family can mediate cross-desensitization of the opioid receptors. Conversely, the opioid receptors are all able to induce heterologous desensitization of some of the chemokine receptors. Consequently, activation of one or more of the opioid receptors can selectively cross-desensitize chemokine receptors and regulate chemokine function. These cross-talk processes have significant implications for the inflammatory response, since the regulation of both the recruitment of inflammatory cells, as well as the sensation of pain, can be controlled in this way.
Topics: Animals; Humans; Receptors, Chemokine; Receptors, Opioid
PubMed: 32076421
DOI: 10.3389/fimmu.2020.00094 -
Nature Reviews. Drug Discovery Mar 2023
Topics: Humans; Receptors, Opioid; Receptors, Opioid, mu; Analgesics, Opioid
PubMed: 36755159
DOI: 10.1038/d41573-023-00022-y -
Pharmacological Research Nov 2023Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs,... (Review)
Review
Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs, antidepressants and SSRI's. Within the opioid family mu and kappa opioid receptor are commonly targeted. However, activation of the mu opioid receptor has side effects of constipation, tolerance, dependence, euphoria, and respiratory depression; activation of the kappa opioid receptor leads to dysphoria and sedation. The side effects of mu opioid receptor activation have led to mu receptor drugs being widely abused with great overdose risk. For these reasons, newer safer opioid analgesics are in high demand. For many years a focus within the opioid field was finding drugs that activated the G protein pathway at mu opioid receptor, without activating the β-arrestin pathway, known as biased agonism. Recent advances have shown that this may not be the way forward to develop safer analgesics at mu opioid receptor, though there is still some promise at the kappa opioid receptor. Here we discuss recent novel approaches to develop safer opioid drugs including efficacy vs bias and fine-tuning receptor activation by targeting sub-pockets in the orthosteric site, we explore recent works on the structural basis of bias, and we put forward the suggestion that Gα subtype selectivity may be an exciting new area of interest.
Topics: Humans; Analgesics, Opioid; Receptors, Opioid, mu; Receptors, Opioid, kappa; Receptors, Opioid; Acute Pain
PubMed: 37844653
DOI: 10.1016/j.phrs.2023.106961 -
Nature Communications Feb 2021Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid...
Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, X-ray crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like opioids remains lacking. Exploiting the X-ray structure of BU72-bound mOR and several molecular simulation techniques, we elucidated the detailed binding mechanism of fentanyl. Surprisingly, in addition to the salt-bridge binding mode common to morphinan opiates, fentanyl can move deeper and form a stable hydrogen bond with the conserved His297, which has been suggested to modulate mOR's ligand affinity and pH dependence by previous mutagenesis experiments. Intriguingly, this secondary binding mode is only accessible when His297 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.
Topics: Analgesics, Opioid; Fentanyl; Ligands; Models, Molecular; Molecular Dynamics Simulation; Morphine; Receptors, Opioid, mu; Structure-Activity Relationship
PubMed: 33579956
DOI: 10.1038/s41467-021-21262-9 -
Molecules (Basel, Switzerland) Sep 2021Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory... (Review)
Review
Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated--methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure-activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.
Topics: Analgesics; Analgesics, Opioid; Animals; Morphinans; Receptors, Opioid, mu; Signal Transduction
PubMed: 34577147
DOI: 10.3390/molecules26185677 -
Molecules (Basel, Switzerland) Oct 2021Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated...
Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKey assay, cADDis cAMP assay, and PathHunter β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKey assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis cAMP and PathHunter β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.
Topics: GTP-Binding Proteins; Gene Expression Regulation; HEK293 Cells; Humans; Molecular Structure; Opioid Peptides; Peptide Fragments; Receptors, Opioid, delta; Receptors, Opioid, mu; Ribulose-Bisphosphate Carboxylase; Signal Transduction; Spinacia oleracea; beta-Arrestins
PubMed: 34641621
DOI: 10.3390/molecules26196079 -
Current Oncology Reports Aug 2021Opioids are still the most effective and widely used treatments for acute and chronic pain in cancer patients. This review focuses on the impact of opioids and mu-opioid... (Review)
Review
PURPOSE OF REVIEW
Opioids are still the most effective and widely used treatments for acute and chronic pain in cancer patients. This review focuses on the impact of opioids and mu-opioid receptors (MOR) on tumor progression and providing new ideas for targeting the MOR in cancer treatment.
RECENT FINDINGS
Studies estimated that opioids facilitate tumor progression and are related to the worse prognosis in cancer patients. As the primary receptor of opioids, MOR is involved in the regulation of malignant transformation of tumors and participating in proliferation, invasion, metastasis, and angiogenesis. MOR may be a new molecular marker of malignant tumors and thus become a new target for cancer therapy, which may be beneficial to the outcomes of cancer patients.
Topics: Analgesics, Opioid; Animals; Disease Progression; Humans; Immunity; Inflammation; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Receptors, Opioid, mu
PubMed: 34342720
DOI: 10.1007/s11912-021-01107-w -
Neuropharmacology Jul 2023The δ opioid receptor (δOR) is a therapeutic target for the treatment of various neurological disorders, such as migraines, chronic pain, alcohol use, and mood... (Review)
Review
The δ opioid receptor (δOR) is a therapeutic target for the treatment of various neurological disorders, such as migraines, chronic pain, alcohol use, and mood disorders. Relative to μ opioid receptor agonists, δOR agonists show lower abuse liability and may be potentially safer analgesic alternatives. However, currently no δOR agonists are approved for clinical use. A small number of δOR agonists reached Phase II trials, but ultimately failed to progress due to lack of efficacy. One side effect of δOR agonism that remains poorly understood is the ability of δOR agonists to produce seizures. The lack of a clear mechanism of action is partly driven by the fact that δOR agonists range in their propensity to induce seizure behavior, with multiple δOR agonists reportedly not causing seizures. There is a significant gap in our current understanding of why certain δOR agonists are more likely to induce seizures, and what signal-transduction pathway and/or brain area is engaged to produce these seizures. In this review we provide a comprehensive overview of the current state of knowledge of δOR agonist-mediated seizures. The review was structured to highlight which agonists produce seizures, which brain regions have been implicated and which signaling mediators have been examined in this behavior. Our hope is that this review will spur future studies that are carefully designed and aimed to solve the question why certain δOR agonists are seizurogenic. Obtaining such insight may expedite the development of novel δOR clinical candidates without the risk of inducing seizures. This article is part of the Special Issue on "Opioid-induced changes in addiction and pain circuits".
Topics: Humans; Receptors, Opioid, delta; Ligands; Brain; Chronic Pain; Seizures; Receptors, Opioid, mu; Analgesics, Opioid
PubMed: 37004753
DOI: 10.1016/j.neuropharm.2023.109526 -
Handbook of Experimental Pharmacology 2022The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system.... (Review)
Review
The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.
Topics: Analgesics, Opioid; Dynorphins; Humans; Ligands; Receptors, Opioid, kappa; Structure-Activity Relationship
PubMed: 33454858
DOI: 10.1007/164_2020_431