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      Endogenous and Exogenous Opioids in Pain

      1 , 2 , 3 , 4 , 5 , 5 , 6 , 7 , 8 , 9 , 1 , 2 , 3 , 4 , 10

      Annual Review of Neuroscience

      Annual Reviews

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          Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

          Summary Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many of their undesirable side effects (sedation, apnea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μOR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the μOR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most GPCRs published to date, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μOR crystallizes as a two-fold symmetric dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.
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            Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry.

             A Basbaum,  H Fields (1983)
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              Structure of the human kappa opioid receptor in complex with JDTic

              Opioid receptors (ORs) mediate the actions of endogenous and exogenous opioids for many essential physiological processes including regulation of pain, respiratory drive, mood, and, in the case of κ-opioid receptors (KOR), dysphoria and psychotomimesis. Here we report the crystal structure of the human KOR (hKOR) in complex with the selective antagonist JDTic, arranged in parallel-dimers, at 2.9 angstrom resolution. The structure reveals important features of the ligand binding pocket that contribute to JDTic’s high affinity and subtype-selectivity for hKOR. Modeling of other important KOR-selective ligands, including the morphinan-derived antagonists nor-BNI and GNTI, and the diterpene agonist salvinorin A analog RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for hKOR subtype-selectivity along with insight essential for the design of hKOR compounds with new pharmacological properties.
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                Author and article information

                Journal
                Annual Review of Neuroscience
                Annu. Rev. Neurosci.
                Annual Reviews
                0147-006X
                1545-4126
                July 08 2018
                July 08 2018
                : 41
                : 1
                : 453-473
                Affiliations
                [1 ]Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, California 94304, USA;
                [2 ]Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, California 94304, USA
                [3 ]Department of Neurosurgery, Stanford University, Palo Alto, California 94304, USA
                [4 ]Stanford Neurosciences Institute, Palo Alto, California 94304, USA
                [5 ]Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63130, USA;
                [6 ]Division of Basic Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63130, USA
                [7 ]Washington University Pain Center, Washington University School of Medicine, St. Louis, Missouri 63130, USA
                [8 ]Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63130, USA
                [9 ]Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA
                [10 ]New York Stem Cell Foundation – Robertson Investigator, Stanford University, Palo Alto, California 94304, USA
                Article
                10.1146/annurev-neuro-080317-061522
                © 2018

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