{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:10:56Z","timestamp":1792001456566,"version":"4.4.0"},"reference-count":149,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T00:00:00Z","timestamp":1600214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DA045884, DA046487"],"award-info":[{"award-number":["DA045884, DA046487"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the \u03bc-opioid receptor (MOR), \u03ba-opioid receptor (KOR), \u03b4-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR\/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting \u03b2-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.<\/jats:p>","DOI":"10.3390\/molecules25184257","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T20:44:13Z","timestamp":1600289053000},"page":"4257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":144,"title":["Biased Opioid Ligands"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9059-4791","authenticated-orcid":false,"given":"Abdelfattah","family":"Faouzi","sequence":"first","affiliation":[{"name":"Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO 63131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balazs R.","family":"Varga","sequence":"additional","affiliation":[{"name":"Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO 63131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susruta","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO 63131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41594-017-0011-7","article-title":"Structure and dynamics of GPCR signaling complexes","volume":"25","author":"Hilger","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.cell.2019.04.021","article-title":"Structural Insights into the Process of GPCR-G Protein Complex Formation","volume":"177","author":"Liu","year":"2019","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/nrd884","article-title":"Value of novelty?","volume":"1","author":"Ma","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.tips.2016.01.001","article-title":"New Technologies for Elucidating Opioid Receptor Function","volume":"37","author":"Bruchas","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1038\/d41586-019-02686-2","article-title":"Tracing the US opioid crisis to its roots","volume":"573","author":"DeWeerdt","year":"2019","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0065-3233(07)74004-4","article-title":"Activation of G Protein\u2013Coupled Receptors","volume":"Volume 74","author":"Deupi","year":"2007","journal-title":"Advances in Protein Chemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1124\/pr.111.004598","article-title":"Functional Selectivity at the -Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance","volume":"63","author":"Raehal","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1515\/bmc-2018-0013","article-title":"Biased receptor functionality versus biased agonism in G-protein-coupled receptors","volume":"9","author":"Franco","year":"2018","journal-title":"Biomol. Concepts"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e136","DOI":"10.1016\/j.bja.2019.03.006","article-title":"Hot topics in opioid pharmacology: Mixed and biased opioids","volume":"122","author":"Azzam","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/s41580-018-0049-3","article-title":"Mechanisms of signalling and biased agonism in G protein-coupled receptors","volume":"19","author":"Wootten","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e650","DOI":"10.1097\/PR9.0000000000000650","article-title":"Biased agonism: The quest for the analgesic holy grail","volume":"3","author":"Stanczyk","year":"2018","journal-title":"PAIN Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Al-Hasani, R., and Bruchas, M.R. (2011). Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior. Anesthesiology, 1.","DOI":"10.1097\/ALN.0b013e318238bba6"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.neuropharm.2018.11.010","article-title":"Arrestin recruitment and signaling by G protein-coupled receptor heteromers","volume":"152","author":"Mores","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.neuron.2011.02.001","article-title":"The Doctor\u2019s Dilemma: Opiate Analgesics and Chronic Pain","volume":"69","author":"Fields","year":"2011","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature10361","article-title":"Crystal structure of the \u03b22 adrenergic receptor\u2013Gs protein complex","volume":"477","author":"Rasmussen","year":"2011","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2017.07.002","article-title":"Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors","volume":"170","author":"Zhou","year":"2017","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1124\/mol.117.110890","article-title":"Biased Agonism in Drug Discovery\u2014Is It Too Soon to Choose a Path?","volume":"93","author":"Michel","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1126\/science.286.5449.2495","article-title":"Enhanced morphine analgesia in mice lacking beta-arrestin 2","volume":"286","author":"Bohn","year":"1999","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/35047086","article-title":"\u03bc-Opioid receptor desensitization by \u03b2-arrestin-2 determines morphine tolerance but not dependence","volume":"408","author":"Bohn","year":"2000","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1124\/jpet.105.087254","article-title":"Morphine Side Effects in -Arrestin 2 Knockout Mice","volume":"314","author":"Raehal","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"954","DOI":"10.3390\/ijms10030954","article-title":"Improvement of Morphine-Mediated Analgesia by Inhibition of \u03b2-Arrestin 2 Expression in Mice Periaqueductal Gray Matter","volume":"10","author":"Li","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1093\/bja\/aer291","article-title":"Antinociceptive potentiation and attenuation of tolerance by intrathecal \u03b2-arrestin 2 small interfering RNA in rats","volume":"107","author":"Yang","year":"2011","journal-title":"Br. J. Anaesth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8019","DOI":"10.1021\/jm4010829","article-title":"Structure\u2013Activity Relationships and Discovery of a G Protein Biased \u03bc Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9 R )-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain","volume":"56","author":"Chen","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nature19112","article-title":"Structure-based discovery of opioid analgesics with reduced side effects","volume":"537","author":"Manglik","year":"2016","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1111\/bph.14913","article-title":"G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder","volume":"177","author":"Gutridge","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaaz3140","DOI":"10.1126\/scisignal.aaz3140","article-title":"Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists","volume":"13","author":"Gillis","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1111\/bph.14224","article-title":"The novel \u03bc-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception: PZM21 depresses respiration","volume":"175","author":"Hill","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6754","DOI":"10.1021\/jacs.6b00360","article-title":"Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators","volume":"138","author":"Kruegel","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8381","DOI":"10.1021\/acs.jmedchem.6b00748","article-title":"Mitragynine\/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit \u03b2-Arrestin-2","volume":"59","author":"Marrone","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1021\/jm701162g","article-title":"Herkinorin Analogues with Differential \u03b2-Arrestin-2 Interactions","volume":"51","author":"Tidgewell","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11027","DOI":"10.1021\/acs.jmedchem.6b01235","article-title":"Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting \u03bc Opioid Analgesic with Reduced Abuse Liability","volume":"59","author":"Crowley","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1021\/acschemneuro.0c00191","article-title":"Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the \u03bc-Opioid Receptor","volume":"11","author":"Crowley","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/j.cell.2017.10.035","article-title":"Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics","volume":"171","author":"Schmid","year":"2017","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8895","DOI":"10.1021\/acs.jmedchem.8b01136","article-title":"Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias","volume":"61","author":"Kennedy","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_35","unstructured":"Commissioner, O. (2020, September 07). FDA Approves New Opioid for Intravenous Use in Hospitals, Other Controlled Clinical Settings, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-new-opioid-intravenous-use-hospitals-other-controlled-clinical-settings."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107718","DOI":"10.1016\/j.neuropharm.2019.107718","article-title":"Biased agonism of clinically approved \u03bc-opioid receptor agonists and TRV130 is not controlled by binding and signaling kinetics","volume":"166","author":"Pedersen","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1213\/ANE.0000000000003662","article-title":"Pharmacological Characters of Oliceridine, a \u03bc-Opioid Receptor G-Protein\u2013Biased Ligand in Mice","volume":"129","author":"Liang","year":"2019","journal-title":"Anesth. Analg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1177\/0269881116689257","article-title":"Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents","volume":"31","author":"Altarifi","year":"2017","journal-title":"J. Psychopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3389\/fnmol.2017.00284","article-title":"Methods Used to Evaluate Pain Behaviors in Rodents","volume":"10","author":"Deuis","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4434","DOI":"10.1111\/bph.14805","article-title":"Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine","volume":"176","author":"Kudla","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/ALN.0000000000002730","article-title":"Mast Cell Degranulation and Fibroblast Activation in the Morphine-induced Spinal Mass: Role of Mas-related G Protein-coupled Receptor Signaling","volume":"131","author":"Yaksh","year":"2019","journal-title":"Anesthesiology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.neubiorev.2012.11.012","article-title":"From Kratom to mitragynine and its derivatives: Physiological and behavioural effects related to use, abuse, and addiction","volume":"37","author":"Hassan","year":"2013","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1016\/j.lfs.2003.09.054","article-title":"Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa","volume":"74","author":"Matsumoto","year":"2004","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.lfs.2004.10.086","article-title":"Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa","volume":"78","author":"Matsumoto","year":"2005","journal-title":"Life Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ejphar.2006.08.013","article-title":"Involvement of \u03bc-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa","volume":"549","author":"Matsumoto","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1021\/acscentsci.9b00141","article-title":"7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects","volume":"5","author":"Kruegel","year":"2019","journal-title":"ACS Cent. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hemby, S.E., McIntosh, S., Leon, F., Cutler, S.J., and McCurdy, C.R. (2018). Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7-hydroxymitragynine: Kratom abuse liability. Addict. Biol.","DOI":"10.1111\/adb.12639"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1124\/mol.106.028258","article-title":"An Opioid Agonist that Does Not Induce \u03bc-Opioid Receptor\u2014Arrestin Interactions or Receptor Internalization","volume":"71","author":"Groer","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_49","first-page":"190","article-title":"Salvinorin A, a kappa-opioid receptor agonist hallucinogen: Pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders","volume":"6","author":"Butelman","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"17457","DOI":"10.1021\/acsomega.9b02244","article-title":"Toward a Universal \u03bc-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands","volume":"4","author":"Wu","year":"2019","journal-title":"ACS Omega"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/d41586-018-00045-1","article-title":"Strategy for making safer opioids bolstered","volume":"553","author":"Majumdar","year":"2018","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1021\/acschemneuro.5b00137","article-title":"Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction","volume":"6","author":"Palmer","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/s41467-018-08162-1","article-title":"Phosphorylation-deficient G-protein-biased \u03bc-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects","volume":"10","author":"Kliewer","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1111\/bph.15004","article-title":"Morphine-induced respiratory depression is independent of \u03b2-arrestin2 signalling","volume":"177","author":"Kliewer","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Beck, T.C., Hapstack, M.A., Beck, K.R., and Dix, T.A. (2019). Therapeutic Potential of Kappa Opioid Agonists. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020095"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1523\/JNEUROSCI.5679-07.2008","article-title":"p38: The Link between the \u03ba-Opioid Receptor and Dysphoria","volume":"28","author":"Carr","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12917","DOI":"10.1523\/JNEUROSCI.2444-15.2015","article-title":"Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons","volume":"35","author":"Ehrich","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"555","DOI":"10.2340\/00015555-1353","article-title":"Systemic Kappa Opioid Receptor Agonists in the Treatment of Chronic Pruritus: A Literature Review","volume":"92","author":"Phan","year":"2012","journal-title":"Acta Derm. Venereol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1124\/jpet.114.216820","article-title":"The G Protein-Biased \u03ba-Opioid Receptor Agonist RB-64 is Analgesic with a Unique Spectrum of Activities In Vivo","volume":"352","author":"White","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kivell, B., Paton, K., Kumar, N., Morani, A., Culverhouse, A., Shepherd, A., Welsh, S., Biggerstaff, A., Crowley, R., and Prisinzano, T. (2018). Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side effects than Salvinorin A in Rodents. Molecules, 23.","DOI":"10.3390\/molecules23102602"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"ra117","DOI":"10.1126\/scisignal.aai8441","article-title":"Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria","volume":"9","author":"Brust","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1111\/bph.13854","article-title":"Selective \u03ba receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice: HS666 produces analgesia without causing aversion","volume":"174","author":"Spetea","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"27050","DOI":"10.1074\/jbc.C112.387332","article-title":"6\u2032-Guanidinonaltrindole (6\u2032-GNTI) Is a G Protein-biased \u03ba-Opioid Receptor Agonist That Inhibits Arrestin Recruitment","volume":"287","author":"Rives","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"22387","DOI":"10.1074\/jbc.M113.476234","article-title":"Functional Selectivity of 6\u2032-Guanidinonaltrindole (6\u2032-GNTI) at \u03ba-Opioid Receptors in Striatal Neurons","volume":"288","author":"Schmid","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"36703","DOI":"10.1074\/jbc.M113.504381","article-title":"Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors","volume":"288","author":"Zhou","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.1073\/pnas.1521825113","article-title":"Collybolide is a novel biased agonist of \u03ba-opioid receptors with potent antipruritic activity","volume":"113","author":"Gupta","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.neulet.2018.02.056","article-title":"Effects of mesyl salvinorin B alone and in combination with naltrexone on alcohol deprivation effect in male and female mice","volume":"673","author":"Zhou","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1021\/acschemneuro.5b00092","article-title":"Structure\u2013Activity Relationship Studies of Functionally Selective Kappa Opioid Receptor Agonists that Modulate ERK 1\/2 Phosphorylation While Preserving G Protein Over \u03b2Arrestin2 Signaling Bias","volume":"6","author":"Lovell","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Shim, W.-S., and Oh, U. (2008). Histamine-Induced Itch and its Relationship with Pain. Mol. Pain, 4.","DOI":"10.1186\/1744-8069-4-29"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1007\/s00213-020-05519-7","article-title":"Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys","volume":"237","author":"Huskinson","year":"2020","journal-title":"Psychopharmacology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"10302","DOI":"10.1021\/jm301258w","article-title":"Discovery and Pharmacological Evaluation of a Diphenethylamine Derivative (HS665), a Highly Potent and Selective \u03ba Opioid Receptor Agonist","volume":"55","author":"Spetea","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/0028-3908(91)90068-M","article-title":"The dopamine D2 agonists RU 24213 and RU 24926 are also KAPPA-opioid receptor antagonists","volume":"30","author":"Fortin","year":"1991","journal-title":"Neuropharmacology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7579","DOI":"10.1021\/acs.jmedchem.7b00981","article-title":"Highly Potent and Selective New Diphenethylamines Interacting with the \u03ba-Opioid Receptor: Synthesis, Pharmacology, and Structure\u2013Activity Relationships","volume":"60","author":"Erli","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Dunn, A., Reed, B., Erazo, J., Ben-Ezra, A., and Kreek, M.J. (2019). Signaling properties of structurally diverse kappa opioid receptor ligands: Towards in vitro models of in vivo responses. ACS Chem. Neurosci., 9b00195.","DOI":"10.1021\/acschemneuro.9b00195"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"9050","DOI":"10.1073\/pnas.0501112102","article-title":"A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers","volume":"102","author":"Waldhoer","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1124\/mol.113.089649","article-title":"Identification of Novel Functionally Selective \u03ba-Opioid Receptor Scaffolds","volume":"85","author":"White","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1111\/bph.13474","article-title":"The G-protein biased partial \u03ba opioid receptor agonist 6\u2032-GNTI blocks hippocampal paroxysmal discharges without inducing aversion: G-protein biased \u03ba-receptor agonists in epilepsy","volume":"173","author":"Zangrandi","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1021\/cc050099b","article-title":"A Concise and Diversity-Oriented Strategy for the Synthesis of Benzofurans and Indoles via Ugi and Diels\u2212Alder Reactions","volume":"7","author":"Lu","year":"2005","journal-title":"J. Comb. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1021\/ml100040t","article-title":"N-Alkyl-octahydroisoquinolin-1-one-8-carboxamides: Selective and Nonbasic \u03ba-Opioid Receptor Ligands","volume":"1","author":"Frankowski","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/S0040-4020(01)97243-6","article-title":"Isolement et analyse structurale du collybolide, nouveau sesquiterpene extrait de Collybia maculata alb. et sch. ex fries (basidiomycetes)","volume":"30","author":"Bui","year":"1974","journal-title":"Tetrahedron"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5188","DOI":"10.1073\/pnas.86.13.5188","article-title":"Deltorphins: A family of naturally occurring peptides with high affinity and selectivity for 6 opioid binding sites","volume":"86","author":"Erspamer","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1111\/j.1460-9568.2008.06223.x","article-title":"Inflammatory pain is enhanced in delta opioid receptor-knockout mice","volume":"27","author":"Karchewski","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"16459","DOI":"10.1523\/JNEUROSCI.3748-10.2010","article-title":"Ligand-Directed Trafficking of the \u03b4-Opioid Receptor In Vivo: Two Paths Toward Analgesic Tolerance","volume":"30","author":"Pradhan","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/76061","article-title":"Mice deficient for \u03b4- and \u03bc-opioid receptors exhibit opposing alterations of emotional responses","volume":"25","author":"Filliol","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tips.2011.06.008","article-title":"The delta opioid receptor: An evolving target for the treatment of brain disorders","volume":"32","author":"Pradhan","year":"2011","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0304-3959(02)00333-0","article-title":"Up-regulation and trafficking of d opioid receptor in a model of chronic inflammation: Implications for pain control","volume":"101","author":"Cahill","year":"2003","journal-title":"Pain"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1111\/j.1600-0854.2010.01145.x","article-title":"The Role of Ubiquitination in Lysosomal Trafficking of \u03b4-Opioid Receptors","volume":"12","author":"Henry","year":"2011","journal-title":"Traffic"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1124\/jpet.108.146969","article-title":"JNJ-20788560 [9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9 H-xanthene-3-carboxylic Acid Diethylamide], a Selective Delta Opioid Receptor Agonist, is a Potent and Efficacious Antihyperalgesic Agent That Does Not Produce Respiratory Depression, Pharmacologic Tolerance, or Physical Dependence","volume":"329","author":"Codd","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s00213-002-1179-y","article-title":"Convulsant activity of a non-peptidic \u03b4-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats","volume":"164","author":"Broom","year":"2002","journal-title":"Psychopharmacology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5376","DOI":"10.1111\/bph.12852","article-title":"In vivo properties of KNT-127, a novel \u03b4 opioid receptor agonist: Receptor internalization, antihyperalgesia and antidepressant effects in mice: KNT-127 ligand-biased agonism at \u03b4 opioid receptor","volume":"171","author":"Nozaki","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1124\/pr.114.008979","article-title":"Molecular Pharmacology of \u03b4-Opioid Receptors","volume":"68","author":"Gendron","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Tian, X., Guo, J., Zhu, M., Li, M., Wu, G., and Xia, Y. (2013). \u03b4-Opioid Receptor Activation Rescues the Functional TrkB Receptor and Protects the Brain from Ischemia-Reperfusion Injury in the Rat. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069252"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nature12944","article-title":"Molecular control of \u03b4-opioid receptor signalling","volume":"506","author":"Fenalti","year":"2014","journal-title":"Nature"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"eaax9115","DOI":"10.1126\/sciadv.aax9115","article-title":"Elucidating the active \u03b4-opioid receptor crystal structure with peptide and small-molecule agonists","volume":"5","author":"Claff","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1111\/j.1471-4159.2009.06082.x","article-title":"G Protein independent phosphorylation and internalization of the \u03b4-opioid receptor","volume":"109","author":"Bradbury","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4259","DOI":"10.1242\/jcs.073742","article-title":"Serine 363 of the \u03b4-opioid receptor is crucial for adopting distinct pathways to activate ERK1\/2 in response to stimulation with different ligands","volume":"123","author":"Xu","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"22315","DOI":"10.1074\/jbc.M611258200","article-title":"Phosphorylation of the \u03b4-Opioid Receptor Regulates Its \u03b2-Arrestins Selectivity and Subsequent Receptor Internalization and Adenylyl Cyclase Desensitization","volume":"282","author":"Qiu","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.cellsig.2011.10.018","article-title":"\u00dfarrestin1-biased agonism at human \u03b4-opioid receptor by peptidic and alkaloid ligands","volume":"24","author":"Aguila","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1124\/mol.59.4.758","article-title":"Direct and differential interaction of beta-arrestins with the intracellular domains of different opioid receptors","volume":"59","author":"Cen","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3541","DOI":"10.1523\/JNEUROSCI.4124-15.2016","article-title":"Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function","volume":"36","author":"Pradhan","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1111\/bph.14353","article-title":"Tolerance to high-internalizing \u03b4 opioid receptor agonist is critically mediated by arrestin 2","volume":"175","author":"Dripps","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/bph.14131","article-title":"Role of signalling molecules in behaviours mediated by the \u03b4 opioid receptor agonist SNC80: Signalling bias and \u03b4-receptor activity","volume":"175","author":"Dripps","year":"2018","journal-title":"In Vivo Br. J. Pharmacol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1111\/j.1476-5381.2012.02075.x","article-title":"Ligand-directed signalling within the opioid receptor family: Ligand-directed signalling at opioid receptors","volume":"167","author":"Pradhan","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"15281","DOI":"10.1073\/pnas.2000500117","article-title":"Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain","volume":"117","author":"Gong","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1124\/jpet.119.258640","article-title":"A Novel G Protein\u2013Biased Agonist at the \u03b4 Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain","volume":"372","author":"Conibear","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ejmech.2019.02.043","article-title":"(2S)-N-2-methoxy-2-phenylethyl-6,7-benzomorphan compound (2S-LP2): Discovery of a biased mu\/delta opioid receptor agonist","volume":"168","author":"Pasquinucci","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/bph.13374","article-title":"\u03b2-Arrestin 2 dependence of \u03b4 opioid receptor agonists is correlated with alcohol intake: Biased \u03b4 receptor agonists for treating alcohol use disorders","volume":"173","author":"Chiang","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1016\/S0024-3205(01)01010-4","article-title":"The pharmacological profile of delta opioid receptor ligands, (+) and (-) TAN-67 on pain modulation","volume":"68","author":"Nagase","year":"2001","journal-title":"Life Sci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1124\/jpet.110.170969","article-title":"Dual Efficacy of Delta Opioid Receptor-Selective Ligands for Ethanol Drinking and Anxiety","volume":"335","author":"Brissett","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6302","DOI":"10.1016\/j.bmcl.2010.08.083","article-title":"Design and synthesis of KNT-127, a \u03b4-opioid receptor agonist effective by systemic administration","volume":"20","author":"Nagase","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.bbr.2011.04.041","article-title":"The novel \u03b4 opioid receptor agonist KNT-127 produces antidepressant-like and antinociceptive effects in mice without producing convulsions","volume":"223","author":"Saitoh","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"231","DOI":"10.2174\/157015912803217314","article-title":"Antidepressant-like Effects of \u03b4 Opioid Receptor Agonists in Animal Models","volume":"10","author":"Saitoh","year":"2012","journal-title":"Curr. Neuropharmacol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Pradhan, A.A.A., Becker, J.A.J., Scherrer, G., Tryoen-Toth, P., Filliol, D., Matifas, A., Massotte, D., Gav\u00e9riaux-Ruff, C., and Kieffer, B.L. (2009). In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of Agonists. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005425"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"22795","DOI":"10.1074\/jbc.M300084200","article-title":"Differential Sorting of Human \u03b4-Opioid Receptors after Internalization by Peptide and Alkaloid Agonists","volume":"278","author":"Marie","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.pharmthera.2013.10.011","article-title":"The biology of Nociceptin\/Orphanin FQ (N\/OFQ) related to obesity, stress, anxiety, mood, and drug dependence","volume":"141","author":"Witkin","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1111\/bph.12744","article-title":"Functional plasticity of the N\/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists: The N\/OFQ-NOP receptor system in analgesia","volume":"171","author":"Lambert","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1213\/01.ane.0000250403.88649.51","article-title":"The Hypnotic, Electroencephalographic, and Antinociceptive Properties of Nonpeptide ORL1 Receptor Agonists after Intravenous Injection in Rodents","volume":"104","author":"Byford","year":"2007","journal-title":"Anesth. Analg."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1097\/ALN.0000000000001530","article-title":"Opioid-type Respiratory Depressant Side Effects of Cebranopadol in Rats Are Limited by Its Nociceptin\/Orphanin FQ Peptide Receptor Agonist Activity","volume":"126","author":"Linz","year":"2017","journal-title":"Anesthesiology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"eaar3483","DOI":"10.1126\/scitranslmed.aar3483","article-title":"A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates","volume":"10","author":"Ding","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1527-3458.2007.00007.x","article-title":"The Pharmacology of Ro 64-6198, a Systemically Active, Nonpeptide NOP Receptor (Opiate Receptor-Like 1, ORL-1) Agonist with Diverse Preclinical Therapeutic Activity","volume":"13","author":"Shoblock","year":"2007","journal-title":"CNS Drug Rev."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.pharmthera.2013.05.008","article-title":"Nociceptin\/orphanin FQ receptor antagonists as innovative antidepressant drugs","volume":"140","author":"Gavioli","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1177\/0269881117691456","article-title":"Effects of [Nphe1, Arg14, Lys15] N\/OFQ-NH2 (UFP-101), a potent NOP receptor antagonist, on molecular, cellular and behavioural alterations associated with chronic mild stress","volume":"31","author":"Vitale","year":"2017","journal-title":"J. Psychopharmacol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.neuropharm.2016.02.003","article-title":"Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin\/orphanin FQ receptor ligands","volume":"105","author":"Asth","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0014-2999(00)00590-2","article-title":"Effect of nociceptin\/orphanin FQ on the rewarding properties of morphine","volume":"404","author":"Ciccocioppo","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/S0196-9781(00)00250-3","article-title":"Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats","volume":"21","author":"Pieretti","year":"2000","journal-title":"Peptides"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Ko, M.-C., and Cal\u00f3, G. (2019). The Nociceptin\/Orphanin FQ Peptide Receptor. Handbook of Experimental Pharmacology, Springer International Publishing.","DOI":"10.1007\/978-3-030-20186-9"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1124\/mol.115.099150","article-title":"Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin\/Orphanin FQ Opioid Receptor","volume":"88","author":"Chang","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"42019","DOI":"10.1074\/jbc.M112.405696","article-title":"Serine 363 Is Required for Nociceptin\/Orphanin FQ Opioid Receptor (NOPR) Desensitization, Internalization, and Arrestin Signaling","volume":"287","author":"Zhang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"eaau8072","DOI":"10.1126\/scisignal.aau8072","article-title":"Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists","volume":"12","author":"Mann","year":"2019","journal-title":"Sci. Signal."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Malfacini, D., Ambrosio, C., Gro\u2019, M.C., Sbraccia, M., Trapella, C., Guerrini, R., Bonora, M., Pinton, P., Costa, T., and Calo\u2019, G. (2015). Pharmacological Profile of Nociceptin\/Orphanin FQ Receptors Interacting with G-Proteins and \u03b2-Arrestins 2. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132865"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1124\/mol.112.084632","article-title":"Cellular Mechanisms of Nociceptin\/Orphanin FQ (N\/OFQ) Peptide (NOP) Receptor Regulation and Heterologous Regulation by N\/OFQ","volume":"83","author":"Donica","year":"2013","journal-title":"Mol. Pharmacol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"23964","DOI":"10.1074\/jbc.M113.474452","article-title":"Ligands Raise the Constraint That Limits Constitutive Activation in G Protein-coupled Opioid Receptors","volume":"288","author":"Vezzi","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"e00247","DOI":"10.1002\/prp2.247","article-title":"Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin\/orphanin FQ and opioid receptor agonist","volume":"4","author":"Rizzi","year":"2016","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"107678","DOI":"10.1016\/j.neuropharm.2019.107678","article-title":"BPR1M97, a dual mu opioid receptor\/nociceptin-orphanin FQ peptide receptor agonist, produces potent antinociceptive effects with safer properties than morphine","volume":"166","author":"Chao","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.ejmech.2016.09.003","article-title":"Discovery, structure-activity relationship studies, and anti-nociceptive effects of N-(1,2,3,4-tetrahydro-1-isoquinolinylmethyl)benzamides as novel opioid receptor agonists","volume":"126","author":"Chen","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1016\/S0960-894X(99)00385-6","article-title":"8-Acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as orphanin FQ receptor agonists","volume":"9","author":"Wichmann","year":"1999","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1177\/0269881119864942","article-title":"Modulation of the NOP receptor signaling affects resilience to acute stress","volume":"33","author":"Holanda","year":"2019","journal-title":"J. Psychopharmacol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1097\/00008877-200205000-00006","article-title":"Orphanin FQ\/nociceptin but not Ro 65-6570 inhibits the expression of cocaine-induced conditioned place preference","volume":"13","author":"Wichmann","year":"2002","journal-title":"Behav. Pharmacol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.ejphar.2010.07.036","article-title":"Effects of the NOP receptor agonist Ro65-6570 on the acquisition of opiate- and psychostimulant-induced conditioned place preference in rats","volume":"645","author":"Rutten","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1124\/jpet.108.136937","article-title":"The Anxiolytic-Like Effects of the Novel, Orally Active Nociceptin Opioid Receptor Agonist 8-[bis(2-Methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)","volume":"326","author":"Varty","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1111\/adb.12550","article-title":"Limited potential of cebranopadol to produce opioid-type physical dependence in rodents: Weak cebranopadol dependence","volume":"23","author":"Tzschentke","year":"2018","journal-title":"Addict. Biol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1111\/papr.12558","article-title":"Antihyperalgesic, Antiallodynic, and Antinociceptive Effects of Cebranopadol, a Novel Potent Nociceptin\/Orphanin FQ and Opioid Receptor Agonist, after Peripheral and Central Administration in Rodent Models of Neuropathic Pain","volume":"17","author":"Tzschentke","year":"2017","journal-title":"Pain Pract."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1254\/jphs.FP0071742","article-title":"Pharmacological Characterization of the Newly Synthesized Nociceptin\/Orphanin FQ\u2013Receptor Agonist 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an Anxiolytic Agent","volume":"106","author":"Hirao","year":"2008","journal-title":"J. Pharmacol. Sci."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/sj.bjp.0703661","article-title":"(8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid methyl ester (NNC 63-0532) is a novel potent nociceptin receptor agonist","volume":"131","author":"Thomsen","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Gillis, A., Sreenivasan, V., and Christie, M.J. (2020). Intrinsic efficacy of opioid ligands and its importance for apparent bias, operational analysis and therapeutic window. Mol. Pharmacol., mol.119.119214.","DOI":"10.1124\/mol.119.119214"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.biopsych.2019.10.020","article-title":"Toward Directing Opioid Receptor Signaling to Refine Opioid Therapeutics","volume":"87","author":"Grim","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.cell.2017.12.011","article-title":"Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor","volume":"172","author":"Che","year":"2018","journal-title":"Cell"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"4001","DOI":"10.1016\/j.bmcl.2011.05.008","article-title":"Generation of novel radiolabeled opiates through site-selective iodination","volume":"21","author":"Majumdar","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1172\/JCI88760","article-title":"Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine","volume":"127","author":"Xu","year":"2017","journal-title":"J. Clin. Investig."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/18\/4257\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:10:42Z","timestamp":1760177442000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/18\/4257"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,16]]},"references-count":149,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["molecules25184257"],"URL":"https:\/\/doi.org\/10.3390\/molecules25184257","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,16]]}}}