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Annual Review of Biochemistry

Volume 90, 2021

Structural Insights Accelerate the Discovery of Opioid Alternatives

Abstract

Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the μ-opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. In this review, we summarize alternative strategies and targets that could be used to develop safer nonopioid analgesics. A molecular understanding of G protein–coupled receptor activation and signaling has illuminated not only the complexities of receptor pharmacology but also the potential for pathway-selective agonists and allosteric modulators as safer medications. The availability of structures of pain-related receptors, in combination with high-throughput computational tools, has accelerated the discovery of multitarget ligands with promising pharmacological profiles. Emerging clinical evidence also supports the notion that drugs targeting peripheral opioid receptors have potential as improved analgesic agents.

Keyword(s): analgesic, GPCR, nonopioid, opioid receptor, opioids, side effects
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/content/journals/10.1146/annurev-biochem-061620-044044
2021-06-20
2024-04-23
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Literature Cited

  1. 1. 
    Pitcher MH, Von Korff M, Bushnell MC, Porter L. 2019. Prevalence and profile of high-impact chronic pain in the United States. J. Pain 20:146–60
     [Google Scholar]
  2. 2. 
    Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S et al. 2018. Prevalence of chronic pain and high-impact chronic pain among adults—United States; 2016. MMWR Morb. Mortal. Wkly. Rep. 67:1001–6
     [Google Scholar]
  3. 3. 
    Bruchas MR, Roth BL. 2016. New technologies for elucidating opioid receptor function. Trends Pharmacol. Sci. 37:279–89
     [Google Scholar]
  4. 4. 
    Hedegaard H, Minino AM, Warner M. 2020. Drug overdose deaths in the United States, 1999–2018 Data Brief 356 Natl. Cent. Health Stat Hyattsville, MD:
  5. 5. 
    Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G 2018. Drug and opioid-involved overdose deaths—United States, 2013–2017. MMWR Morb. Mortal. Wkly. Rep. 67:1419–27
     [Google Scholar]
  6. 6. 
    Volkow ND, Collins FS. 2017. The role of science in addressing the opioid crisis. N. Engl. J. Med. 377:391–94
     [Google Scholar]
  7. 7. 
    Basbaum AI, Bautista DM, Scherrer G, Julius D 2009. Cellular and molecular mechanisms of pain. Cell 139:267–84
     [Google Scholar]
  8. 8. 
    Braz J, Solorzano C, Wang X, Basbaum AI 2014. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82:522–36
     [Google Scholar]
  9. 9. 
    Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S et al. 1996. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the μ-opioid-receptor gene. Nature 383:819–23
     [Google Scholar]
  10. 10. 
    Wang D, Tawfik VL, Corder G, Low SA, Francois A et al. 2018. Functional divergence of delta and mu opioid receptor organization in CNS pain circuits. Neuron 98:90–108.e5
     [Google Scholar]
  11. 11. 
    Corder G, Ahanonu B, Grewe BF, Wang D, Schnitzer MJ, Scherrer G. 2019. An amygdalar neural ensemble that encodes the unpleasantness of pain. Science 363:276–81
     [Google Scholar]
  12. 12. 
    Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. 1976. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther. 197:517–32
     [Google Scholar]
  13. 13. 
    Millan MJ. 1990. κ-Opioid receptors and analgesia. Trends Pharmacol. Sci. 11:70–76
     [Google Scholar]
  14. 14. 
    Gaveriaux-Ruff C, Nozaki C, Nadal X, Hever XC, Weibel R et al. 2011. Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain 152:1238–48
     [Google Scholar]
  15. 15. 
    Ko MC, Naughton NN. 2009. Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys. J. Pain 10:509–16
     [Google Scholar]
  16. 16. 
    Ko MC, Woods JH, Fantegrossi WE, Galuska CM, Wichmann J, Prinssen EP. 2009. Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys. Neuropsychopharmacology 34:2088–96
     [Google Scholar]
  17. 17. 
    Costigan M, Woolf CJ. 2000. Pain: molecular mechanisms. J. Pain 1:35–44
     [Google Scholar]
  18. 18. 
    Wanderer JP, Nathan N. 2017. Molecular targets for pain management: more than just mu. Anesth. Analg. 125:1427
     [Google Scholar]
  19. 19. 
    DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL et al. 2013. A G protein–biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344:708–17
     [Google Scholar]
  20. 20. 
    Altarifi AA, David B, Muchhala KH, Blough BE, Akbarali H, Negus SS. 2017. 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. J. Psychopharmacol. 31:730–39
     [Google Scholar]
  21. 21. 
    Zamarripa CA, Edwards SR, Qureshi HN, Yi JN, Blough BE, Freeman KB. 2018. The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats. Drug Alcohol Depend. 192:158–62
     [Google Scholar]
  22. 22. 
    Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D et al. 2016. Structure-based discovery of opioid analgesics with reduced side effects. Nature 537:185–90
     [Google Scholar]
  23. 23. 
    Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD et al. 2020. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci. Signal. 13:eaaz3140
     [Google Scholar]
  24. 24. 
    Schmid CL, Kennedy NM, Ross NC, Lovell KM, Yue Z et al. 2017. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171:1165–75.e13
     [Google Scholar]
  25. 25. 
    Schattauer SS, Kuhar JR, Song A, Chavkin C. 2017. Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor. Cell. Signal. 32:59–65
     [Google Scholar]
  26. 26. 
    White KL, Robinson JE, Zhu H, DiBerto JF, Polepally PR et al. 2015. The G protein–biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J. Pharmacol. Exp. Ther. 352:98–109
     [Google Scholar]
  27. 27. 
    Brust TF, Morgenweck J, Kim SA, Rose JH, Locke JL et al. 2016. Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci. Signal. 9:ra117
     [Google Scholar]
  28. 28. 
    Burford NT, Livingston KE, Canals M, Ryan MR, Budenholzer LM et al. 2015. Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor. J. Med. Chem. 58:4220–29
     [Google Scholar]
  29. 29. 
    Bisignano P, Burford NT, Shang Y, Marlow B, Livingston KE et al. 2015. Ligand-based discovery of a new scaffold for allosteric modulation of the μ-opioid receptor. J. Chem. Inf. Model. 55:1836–43
     [Google Scholar]
  30. 30. 
    Stanczyk MA, Livingston KE, Chang L, Weinberg ZY, Puthenveedu MA, Traynor JR. 2019. The δ-opioid receptor positive allosteric modulator BMS 986187 is a G-protein-biased allosteric agonist. Br. J. Pharmacol. 176:1649–63
     [Google Scholar]
  31. 31. 
    Fenalti G, Giguere PM, Katritch V, Huang XP, Thompson AA et al. 2014. Molecular control of δ-opioid receptor signalling. Nature 506:191–96
     [Google Scholar]
  32. 32. 
    Che T, English J, Krumm BE, Kim K, Pardon E et al. 2020. Nanobody-enabled monitoring of kappa opioid receptor states. Nat. Commun. 11:1145
     [Google Scholar]
  33. 33. 
    Ding H, Kiguchi N, Yasuda D, Daga PR, Polgar WE et al. 2018. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci. Transl. Med. 10:eaar3483
     [Google Scholar]
  34. 34. 
    Yamamoto T, Nair P, Ma SW, Davis P, Yamamura HI et al. 2009. The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety. Bioorg. Med. Chem. 17:7337–43
     [Google Scholar]
  35. 35. 
    Largent-Milnes TM, Brookshire SW, Skinner DP Jr., Hanlon KE, Giuvelis D et al. 2013. Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects. J. Pharmacol. Exp. Ther. 347:7–19
     [Google Scholar]
  36. 36. 
    Fishbane S, Jamal A, Munera C, Wen W, Menzaghi FKALM-1 Trial Investig 2020. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N. Engl. J. Med. 382:222–32
     [Google Scholar]
  37. 37. 
    Spahn V, Del Vecchio G, Labuz D, Rodriguez-Gaztelumendi A, Massaly N et al. 2017. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 355:966–69
     [Google Scholar]
  38. 38. 
    Beckett AH, Casy AF. 1954. Synthetic analgesics: stereochemical considerations. J. Pharm. Pharmacol. 6:986–1001
     [Google Scholar]
  39. 39. 
    Portoghese PS. 1965. A new concept on the mode of interaction of narcotic analgesics with receptors. J. Med. Chem. 8:609–16
     [Google Scholar]
  40. 40. 
    Pasternak GW, Pan YX. 2013. Mu opioids and their receptors: evolution of a concept. Pharmacol. Rev. 65:1257–317
     [Google Scholar]
  41. 41. 
    Pert CB, Snyder SH. 1973. Opiate receptor: demonstration in nervous tissue. Science 179:1011–14
     [Google Scholar]
  42. 42. 
    Evans CJ, Keith DE Jr., Morrison H, Magendzo K, Edwards RH. 1992. Cloning of a delta opioid receptor by functional expression. Science 258:1952–55
     [Google Scholar]
  43. 43. 
    Chen Y, Mestek A, Liu J, Hurley JA, Yu L 1993. Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Mol. Pharmacol. 44:8–12
     [Google Scholar]
  44. 44. 
    Chen Y, Mestek A, Liu J, Yu L 1993. Molecular cloning of a rat κ opioid receptor reveals sequence similarities to the μ and δ opioid receptors. Biochem. J. 295:Part 3625–28
     [Google Scholar]
  45. 45. 
    Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C et al. 1994. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 341:33–38
     [Google Scholar]
  46. 46. 
    Wu H, Wacker D, Mileni M, Katritch V, Han GW et al. 2012. Structure of the human κ-opioid receptor in complex with JDTic. Nature 485:327–32
     [Google Scholar]
  47. 47. 
    Thompson AA, Liu W, Chun E, Katritch V, Wu H et al. 2012. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485:395–99
     [Google Scholar]
  48. 48. 
    Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS et al. 2012. Structure of the δ-opioid receptor bound to naltrindole. Nature 485:400–4
     [Google Scholar]
  49. 49. 
    Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM et al. 2012. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485:321–26
     [Google Scholar]
  50. 50. 
    Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN et al. 2015. Structural insights into μ-opioid receptor activation. Nature 524:315–21
     [Google Scholar]
  51. 51. 
    Koehl A, Hu H, Maeda S, Zhang Y, Qu Q et al. 2018. Structure of the μ-opioid receptor-Gi protein complex. Nature 558:547–52
     [Google Scholar]
  52. 52. 
    Che T, Majumdar S, Zaidi SA, Ondachi P, McCorvy JD et al. 2018. Structure of the nanobody-stabilized active state of the kappa opioid receptor. Cell 172:55–67.e15
     [Google Scholar]
  53. 53. 
    Pfeiffer A, Brantl V, Herz A, Emrich HM. 1986. Psychotomimesis mediated by kappa opiate receptors. Science 233:774–76
     [Google Scholar]
  54. 54. 
    Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC et al. 2002. Salvinorin A: a potent naturally occurring nonnitrogenous κ opioid selective agonist. PNAS 99:11934–39
     [Google Scholar]
  55. 55. 
    Bruchas MR, Land BB, Aita M, Xu M, Barot SK et al. 2007. Stress-induced p38 mitogen-activated protein kinase activation mediates κ-opioid-dependent dysphoria. J. Neurosci. 27:11614–23
     [Google Scholar]
  56. 56. 
    Bruchas MR, Macey TA, Lowe JD, Chavkin C. 2006. Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. J. Biol. Chem. 281:18081–89
     [Google Scholar]
  57. 57. 
    Bruchas MR, Chavkin C. 2010. Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology 210:137–47
     [Google Scholar]
  58. 58. 
    White KL, Scopton AP, Rives ML, Bikbulatov RV, Polepally PR et al. 2014. Identification of novel functionally selective κ-opioid receptor scaffolds. Mol. Pharmacol. 85:83–90
     [Google Scholar]
  59. 59. 
    Ho JH, Stahl EL, Schmid CL, Scarry SM, Aube J, Bohn LM 2018. G protein signaling-biased agonism at the κ-opioid receptor is maintained in striatal neurons. Sci. Signal. 11:eaar4309
     [Google Scholar]
  60. 60. 
    Wikstrom B, Gellert R, Ladefoged SD, Danda Y, Akai M et al. 2005. κ-Opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J. Am. Soc. Nephrol. 16:3742–47
     [Google Scholar]
  61. 61. 
    Erlandson SC, McMahon C, Kruse AC. 2018. Structural basis for G protein–coupled receptor signaling. Annu. Rev. Biophys. 47:1–18
     [Google Scholar]
  62. 62. 
    Weis WI, Kobilka BK. 2018. The molecular basis of G protein–coupled receptor activation. Annu. Rev. Biochem. 87:897–919
     [Google Scholar]
  63. 63. 
    Wootten D, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM. 2018. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 19:638–53
     [Google Scholar]
  64. 64. 
    Wacker D, Stevens RC, Roth BL. 2017. How ligands illuminate GPCR molecular pharmacology. Cell 170:414–27
     [Google Scholar]
  65. 65. 
    Ballesteros JA, Weinstein H. 1995. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci 25:366–428
     [Google Scholar]
  66. 66. 
    Fenalti G, Zatsepin NA, Betti C, Giguere P, Han GW et al. 2015. Structural basis for bifunctional peptide recognition at human δ-opioid receptor. Nat. Struct. Mol. Biol. 22:265–68
     [Google Scholar]
  67. 67. 
    Vardy E, Mosier PD, Frankowski KJ, Wu H, Katritch V et al. 2013. Chemotype-selective modes of action of κ-opioid receptor agonists. J. Biol. Chem. 288:34470–83
     [Google Scholar]
  68. 68. 
    Sheffler DJ, Roth BL. 2003. Salvinorin A: the “magic mint” hallucinogen finds a molecular target in the kappa opioid receptor. Trends Pharmacol. Sci. 24:107–9
     [Google Scholar]
  69. 69. 
    O'Connor C, White KL, Doncescu N, Didenko T, Roth BL et al. 2015. NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor. PNAS 112:11852–57
     [Google Scholar]
  70. 70. 
    Negri A, Rives ML, Caspers MJ, Prisinzano TE, Javitch JA, Filizola M. 2013. Discovery of a novel selective kappa-opioid receptor agonist using crystal structure-based virtual screening. J. Chem. Inf. Model. 53:521–26
     [Google Scholar]
  71. 71. 
    Wang S, Wacker D, Levit A, Che T, Betz RM et al. 2017. D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358:381–86
     [Google Scholar]
  72. 72. 
    Lyu J, Wang S, Balius TE, Singh I, Levit A et al. 2019. Ultra-large library docking for discovering new chemotypes. Nature 566:224–29
     [Google Scholar]
  73. 73. 
    Stein RM, Kang HJ, McCorvy JD, Glatfelter GC, Jones AJ et al. 2020. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature 579:609–14
     [Google Scholar]
  74. 74. 
    Sheldon RJ, Nunan L, Porreca F. 1987. Mu antagonist properties of kappa agonists in a model of rat urinary bladder motility in vivo. J. Pharmacol. Exp. Ther. 243:234–40
     [Google Scholar]
  75. 75. 
    Husbands SM, Neilan CL, Broadbear J, Grundt P, Breeden S et al. 2005. BU74, a complex oripavine derivative with potent kappa opioid receptor agonism and delayed opioid antagonism. Eur. J. Pharmacol. 509:117–25
     [Google Scholar]
  76. 76. 
    Lee KO, Akil H, Woods JH, Traynor JR. 1999. Differential binding properties of oripavines at cloned μ- and δ-opioid receptors. Eur. J. Pharmacol. 378:323–30
     [Google Scholar]
  77. 77. 
    Bouvier M, Hausdorff WP, De Blasi A, O'Dowd BF, Kobilka BK et al. 1988. Removal of phosphorylation sites from the β2-adrenergic receptor delays onset of agonist-promoted desensitization. Nature 333:370–73
     [Google Scholar]
  78. 78. 
    Lohse M, Benovic J, Codina J, Caron M, Lefkowitz R 1990. Beta-arrestin: a protein that regulates beta-adrenergic receptor function. Science 248:1547–50
     [Google Scholar]
  79. 79. 
    Cooper DM, Londos C, Gill DL, Rodbell M. 1982. Opiate receptor-mediated inhibition of adenylate cyclase in rat striatal plasma membranes. J. Neurochem. 38:1164–67
     [Google Scholar]
  80. 80. 
    Seward E, Hammond C, Henderson G. 1991. μ-Opioid-receptor-mediated inhibition of the N-type calcium-channel current. Proc. Biol. Sci. 244:129–35
     [Google Scholar]
  81. 81. 
    Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C 1995. Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes. Mol. Pharmacol. 47:551–57
     [Google Scholar]
  82. 82. 
    Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ. 1989. Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Science 246:235–40
     [Google Scholar]
  83. 83. 
    Kwatra MM, Benovic JL, Caron MG, Lefkowitz RJ, Hosey MM. 1989. Phosphorylation of chick heart muscarinic cholinergic receptors by the β-adrenergic receptor kinase. Biochemistry 28:4543–47
     [Google Scholar]
  84. 84. 
    Appleyard SM, Celver J, Pineda V, Kovoor A, Wayman GA, Chavkin C. 1999. Agonist-dependent desensitization of the κ opioid receptor by G protein receptor kinase and β-arrestin. J. Biol. Chem. 274:23802–7
     [Google Scholar]
  85. 85. 
    Kovoor A, Nappey V, Kieffer BL, Chavkin C. 1997. μ and δ opioid receptors are differentially desensitized by the coexpression of β-adrenergic receptor kinase 2 and β-arrestin 2 in Xenopus oocytes. J. Biol. Chem. 272:27605–11
     [Google Scholar]
  86. 86. 
    Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ. 1990. beta-Arrestin: a protein that regulates beta-adrenergic receptor function. Science 248:1547–50
     [Google Scholar]
  87. 87. 
    Whistler JL, von Zastrow M 1998. Morphine-activated opioid receptors elude desensitization by β-arrestin. PNAS 95:9914–19
     [Google Scholar]
  88. 88. 
    Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME et al. 2001. Activation and targeting of extracellular signal-regulated kinases by β-arrestin scaffolds. PNAS 98:2449–54
     [Google Scholar]
  89. 89. 
    Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S et al. 1999. β-Arrestin-dependent formation of β2 adrenergic receptor-Src protein kinase complexes. Science 283:655–61
     [Google Scholar]
  90. 90. 
    Roth BL, Chuang DM. 1987. Multiple mechanisms of serotonergic signal transduction. Life Sci 41:1051–64
     [Google Scholar]
  91. 91. 
    Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B et al. 2007. Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther. 320:1–13
     [Google Scholar]
  92. 92. 
    Jarpe MB, Knall C, Mitchell FM, Buhl AM, Duzic E, Johnson GL. 1998. [d-Arg1,d-Phe5,d-Trp7,9,Leu11]Substance P acts as a biased agonist toward neuropeptide and chemokine receptors. J. Biol. Chem. 273:3097–104
     [Google Scholar]
  93. 93. 
    Raehal KM, Walker JK, Bohn LM. 2005. Morphine side effects in β-arrestin 2 knockout mice. J. Pharmacol. Exp. Ther. 314:1195–201
     [Google Scholar]
  94. 94. 
    Morgenweck J, Frankowski KJ, Prisinzano TE, Aube J, Bohn LM 2015. Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus. Neuropharmacology 99:600–9
     [Google Scholar]
  95. 95. 
    Huskinson SL, Platt DM, Brasfield M, Follett ME, Prisinzano TE et al. 2020. Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys. Psychopharmacology 237:2075–87
     [Google Scholar]
  96. 96. 
    Kliewer A, Schmiedel F, Sianati S, Bailey A, Bateman JT et al. 2019. Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects. Nat. Commun. 10:367
     [Google Scholar]
  97. 97. 
    Kliewer A, Gillis A, Hill R, Schmidel F, Bailey C et al. 2020. Morphine-induced respiratory depression is independent of β-arrestin2 signalling. Br. J. Pharmacol. 177:2923–31
     [Google Scholar]
  98. 98. 
    Montandon G, Liu H, Horner RL. 2016. Contribution of the respiratory network to rhythm and motor output revealed by modulation of GIRK channels, somatostatin and neurokinin-1 receptors. Sci. Rep. 6:32707
     [Google Scholar]
  99. 99. 
    Li Y, van den Pol AN. 2008. μ-Opioid receptor-mediated depression of the hypothalamic hypocretin/orexin arousal system. J. Neurosci. 28:2814–19
     [Google Scholar]
  100. 100. 
    Galligan JJ, Akbarali HI. 2014. Molecular physiology of enteric opioid receptors. Am. J. Gastroenterol. Suppl. 2:17–21
     [Google Scholar]
  101. 101. 
    Sesena E, Vega R, Soto E. 2014. Activation of μ-opioid receptors inhibits calcium-currents in the vestibular afferent neurons of the rat through a cAMP dependent mechanism. Front. Cell Neurosci. 8:90
     [Google Scholar]
  102. 102. 
    Dripps IJ, Boyer BT, Neubig RR, Rice KC, Traynor JR, Jutkiewicz EM. 2018. Role of signalling molecules in behaviours mediated by the δ opioid receptor agonist SNC80. Br. J. Pharmacol. 175:891–901
     [Google Scholar]
  103. 103. 
    Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C. 2008. The dysphoric component of stress is encoded by activation of the dynorphin κ-opioid system. J. Neurosci. 28:407–14
     [Google Scholar]
  104. 104. 
    Bruchas MR, Xu M, Chavkin C. 2008. Repeated swim-stress induces kappa opioid-mediated activation of ERK1/2 MAPK. NeuroReport 19:1417–22
     [Google Scholar]
  105. 105. 
    Ehrich JM, Messinger DI, Knakal CR, Kuhar JR, Schattauer SS et al. 2015. Kappa opioid receptor-induced aversion requires p38 MAPK activation in VTA dopamine neurons. J. Neurosci. 35:12917–31
     [Google Scholar]
  106. 106. 
    Liu JJ, Sharma K, Zangrandi L, Chen C, Humphrey SJ et al. 2018. In vivo brain GPCR signaling elucidated by phosphoproteomics. Science 360:eaao4927
     [Google Scholar]
  107. 107. 
    Liu JJ, Chiu YT, DiMattio KM, Chen C, Huang P et al. 2018. Phosphoproteomic approach for agonist-specific signaling in mouse brains: mTOR pathway is involved in κ opioid aversion. Neuropsychopharmacology 44:939–49
     [Google Scholar]
  108. 108. 
    Olsen RHJ, DiBerto JF, English JG, Glaudin AM, Krumm BE et al. 2020. TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat. Chem. Biol. 16:841–49
     [Google Scholar]
  109. 109. 
    Benredjem B, Gallion J, Pelletier D, Dallaire P, Charbonneau J et al. 2019. Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response. Nat. Commun. 10:4075
     [Google Scholar]
  110. 110. 
    Luttrell LM, Wang J, Plouffe B, Smith JS, Yamani L et al. 2018. Manifold roles of β-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9. Sci. Signal. 11:eaat7650
     [Google Scholar]
  111. 111. 
    Thal DM, Glukhova A, Sexton PM, Christopoulos A. 2018. Structural insights into G-protein-coupled receptor allostery. Nature 559:45–53
     [Google Scholar]
  112. 112. 
    Pert CB, Pasternak G, Snyder SH. 1973. Opiate agonists and antagonists discriminated by receptor binding in brain. Science 182:1359–61
     [Google Scholar]
  113. 113. 
    Pasternak GW, Snowman AM, Snyder SH. 1975. Selective enhancement of [3H]opiate agonist binding by divalent cations. Mol. Pharmacol. 11:735–44
     [Google Scholar]
  114. 114. 
    Kimura KT, Asada H, Inoue A, Kadji FMN, Im D et al. 2019. Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine. Nat. Struct. Mol. Biol. 26:121–28
     [Google Scholar]
  115. 115. 
    Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH et al. 2020. Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding. Science 368:428–33
     [Google Scholar]
  116. 116. 
    Lefkowitz R, Cotecchia S, Samama P, Costa T. 1993. Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol. Sci. 14:303–7
     [Google Scholar]
  117. 117. 
    Burford NT, Traynor JR, Alt A. 2015. Positive allosteric modulators of the μ-opioid receptor: a novel approach for future pain medications. Br. J. Pharmacol. 172:277–86
     [Google Scholar]
  118. 118. 
    Korczynska M, Clark MJ, Valant C, Xu J, Moo EV et al. 2018. Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor. PNAS 115:E2419–28
     [Google Scholar]
  119. 119. 
    Huang XP, Karpiak J, Kroeze WK, Zhu H, Chen X et al. 2015. Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527:477–83
     [Google Scholar]
  120. 120. 
    Shang Y, Yeatman HR, Provasi D, Alt A, Christopoulos A et al. 2016. Proposed mode of binding and action of positive allosteric modulators at opioid receptors. ACS Chem. Biol. 11:1220–29
     [Google Scholar]
  121. 121. 
    Hori T, Okuno T, Hirata K, Yamashita K, Kawano Y et al. 2018. Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1. Nat. Chem. Biol. 14:262–69
     [Google Scholar]
  122. 122. 
    Roth BL, Sheffler DJ, Kroeze WK. 2004. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3:353–59
     [Google Scholar]
  123. 123. 
    Lansu K, Karpiak J, Liu J, Huang XP, McCorvy JD et al. 2017. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat. Chem. Biol. 13:529–36
     [Google Scholar]
  124. 124. 
    Gunther T, Dasgupta P, Mann A, Miess E, Kliewer A et al. 2018. Targeting multiple opioid receptors—improved analgesics with reduced side effects?. Br. J. Pharmacol. 175:2857–68
     [Google Scholar]
  125. 125. 
    Machelska H, Celik MO. 2018. Advances in achieving opioid analgesia without side effects. Front. Pharmacol. 9:1388
     [Google Scholar]
  126. 126. 
    Besnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM et al. 2012. Automated design of ligands to polypharmacological profiles. Nature 492:215–20
     [Google Scholar]
  127. 127. 
    Burness CB, Keating GM. 2014. Oxycodone/naloxone prolonged-release: a review of its use in the management of chronic pain while counteracting opioid-induced constipation. Drugs 74:353–75
     [Google Scholar]
  128. 128. 
    Stein C. 2018. New concepts in opioid analgesia. Expert Opin. Investig. Drugs 27:765–75
     [Google Scholar]
  129. 129. 
    Podolsky AT, Sandweiss A, Hu J, Bilsky EJ, Cain JP et al. 2013. Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain. Life Sci 93:1010–16
     [Google Scholar]
  130. 130. 
    Varadi A, Hosztafi S, Le Rouzic V, Toth G, Urai A et al. 2013. Novel 6β-acylaminomorphinans with analgesic activity. Eur. J. Med. Chem. 69:786–89
     [Google Scholar]
  131. 131. 
    Nakao K, Hirakata M, Miyamoto Y, Kainoh M, Wakasa Y, Yanagita T. 2016. Nalfurafine hydrochloride, a selective κ opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys. J. Pharmacol. Sci. 130:8–14
     [Google Scholar]
  132. 132. 
    Morphy R, Rankovic Z. 2005. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem. 48:6523–43
     [Google Scholar]
  133. 133. 
    Starnowska J, Costante R, Guillemyn K, Popiolek-Barczyk K, Chung NN et al. 2017. Analgesic properties of opioid/NK1 multitarget ligands with distinct in vitro profiles in naive and chronic constriction injury mice. ACS Chem. Neurosci. 8:2315–24
     [Google Scholar]
  134. 134. 
    Gorgulla C, Boeszoermenyi A, Wang ZF, Fischer PD, Coote PW et al. 2020. An open-source drug discovery platform enables ultra-large virtual screens. Nature 580:663–68
     [Google Scholar]
  135. 135. 
    Weiss DR, Karpiak J, Huang XP, Sassano MF, Lyu J et al. 2018. Selectivity challenges in docking screens for GPCR targets and antitargets. J. Med. Chem. 61:6830–45
     [Google Scholar]
  136. 136. 
    Gomes I, Fujita W, Gupta A, Saldanha SA, Negri A et al. 2013. Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity. PNAS 110:12072–77
     [Google Scholar]
  137. 137. 
    Erbs E, Faget L, Scherrer G, Matifas A, Filliol D et al. 2015. A mu–delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct. Funct. 220:677–702
     [Google Scholar]
  138. 138. 
    Koehl A, Hu H, Feng D, Sun B, Zhang Y et al. 2019. Structural insights into the activation of metabotropic glutamate receptors. Nature 566:79–84
     [Google Scholar]
  139. 139. 
    Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. 2014. Naloxegol for opioid-induced constipation in patients with noncancer pain. N. Engl. J. Med. 370:2387–96
     [Google Scholar]
  140. 140. 
    Mangel AW, Hicks GA. 2012. Asimadoline and its potential for the treatment of diarrhea-predominant irritable bowel syndrome: a review. Clin. Exp. Gastroenterol. 5:1–10
     [Google Scholar]
  141. 141. 
    Foxx-Orenstein AE. 2016. New and emerging therapies for the treatment of irritable bowel syndrome: an update for gastroenterologists. Therap. Adv. Gastroenterol. 9:354–75
     [Google Scholar]
  142. 142. 
    Cowan A, Kehner GB, Inan S. 2015. Targeting itch with ligands selective for κ opioid receptors. Handb. Exp. Pharmacol. 226:291–314
     [Google Scholar]
  143. 143. 
    Davenport AP, Scully CCG, de Graaf C, Brown A, Maguire JM. 2020. Advances in therapeutic peptides targeting G protein-coupled receptors. Nat. Rev. Drug Discov. 19:389–413
     [Google Scholar]
  144. 144. 
    Hua S, Cabot PJ. 2013. Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition. Pain Phys 16:E199–216
     [Google Scholar]
  145. 145. 
    Rosas R Jr., Huang XP, Roth BL, Dockendorff C. 2019. β-Fluorofentanyls are pH-sensitive mu opioid receptor agonists. ACS Med. Chem. Lett. 10:1353–56
     [Google Scholar]
  146. 146. 
    Gonzalez-Rodriguez S, Quadir MA, Gupta S, Walker KA, Zhang X et al. 2017. Polyglycerol-opioid conjugate produces analgesia devoid of side effects. eLife 6:e27081
     [Google Scholar]
  147. 147. 
    Le Guen S, Mas Nieto M, Canestrelli C, Chen H, Fournié-Zaluski MC et al. 2003. Pain management by a new series of dual inhibitors of enkephalin degrading enzymes: long lasting antinociceptive properties and potentiation by CCK2 antagonist or methadone. Pain 104:139–48
     [Google Scholar]
  148. 148. 
    Schreiter A, Gore C, Labuz D, Fournié-Zaluski MC, Roques BP et al. 2012. Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB J 26:5161–71
     [Google Scholar]
/content/journals/10.1146/annurev-biochem-061620-044044
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Structural Insights Accelerate the Discovery of Opioid Alternatives
Annual Review of Biochemistry 90, 739 (2021); https://doi.org/10.1146/annurev-biochem-061620-044044
/content/journals/10.1146/annurev-biochem-061620-044044
/content/journals/10.1146/annurev-biochem-061620-044044
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