Positive allosteric modulators of the μ-opioid receptor: A novel approach for future pain medications

British Journal of Pharmacology

Volumn 172, Issue 2, 2015, Pages 277-286

  Burford, N T ^a   Traynor, J R ^b   Alt, A ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

allosteric; arrestin; dependence; ligand bias; modulator; opiate; opioid; pain; receptor; tolerance

Indexed keywords

BMS 986121; BMS 986122; MORPHINE; MU OPIATE RECEPTOR; MU OPIOID RECEPTOR POSITIVE ALLOSTERIC MODULATOR; OPIATE RECEPTOR AFFECTING AGENT; SALVINORIN A; UNCLASSIFIED DRUG; LIGAND; NARCOTIC ANALGESIC AGENT;

ALLOSTERISM; BINDING SITE; CHEMICAL STRUCTURE; DRUG ACTIVITY; DRUG BINDING; DRUG DEVELOPMENT; DRUG POTENCY; DRUG SELECTIVITY; HUMAN; NONHUMAN; ORTHOSTERIC LIGAND; PAIN; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; AGONISTS; ANIMAL; METABOLISM;

ALLOSTERIC REGULATION; ANALGESICS, OPIOID; ANIMALS; HUMANS; LIGANDS; PAIN; RECEPTORS, OPIOID, MU;

EID: 84920156416     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12599     Document Type: Review

References (95)

1. Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA, Harmar AJ, and CGTP Collaborators (2013). The Concise Guide to PHARMACOLOGY 2013/14: G-Protein Coupled Receptors. Br J Pharmacol 170: 1459-1581.
2. Bailey CP, Connor M, (2005). Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol 5: 60-68.
3. Bassoni DL, Raab WJ, Achacoso PL, Loh CY, Wehrman TS, (2012). Measurements of beta-arrestin recruitment to activated seven transmembrane receptors using enzyme complementation. Methods Mol Biol 897: 181-203.
4. Bian JM, Wu N, Su RB, Li J, (2012). Opioid receptor trafficking and signaling: what happens after opioid receptor activation? Cell Mol Neurobiol 32: 167-184.
5. Birdsall NJ, Lazareno S, (2005). Allosterism at muscarinic receptors: ligands and mechanisms. Mini Rev Med Chem 5: 523-543.
6. Black JW, Leff P, (1983). Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci 220: 141-162.
7. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT, (1999). Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286: 2495-2498.
8. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG, (2000). Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408: 720-723.
9. Bruns RF, Fergus JH, (1990). Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes. Mol Pharmacol 38: 939-949.
10. Burford NT, Tolbert LM, Sadee W, (1998). Specific G protein activation and mu-opioid receptor internalization caused by morphine, DAMGO and endomorphin I. Eur J Pharmacol 342: 123-126.
11. Burford NT, Watson J, Bertekap R, Alt A, (2011). Strategies for the identification of allosteric modulators of G-protein-coupled receptors. Biochem Pharmacol 81: 691-702.
12. Burford NT, Clark MJ, Wehrman TS, Gerritz SW, Banks M, O'Connell J, et al. (2013). Discovery of positive allosteric modulators and silent allosteric modulators of the mu-opioid receptor. Proc Natl Acad Sci U S A 110: 10830-10835.
13. 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.
14. Christopoulos A, Kenakin T, (2002). G protein-coupled receptor allosterism and complexing. Pharmacol Rev 54: 323-374.
15. Clark AL, Mitchelson F, (1976). The inhibitory effect of gallamine on muscarinic receptors. Br J Pharmacol 58: 323-331.
16. Conn PJ, Christopoulos A, Lindsley CW, (2009a). Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8: 41-54.
17. Conn PJ, Jones CK, Lindsley CW, (2009b). Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci 30: 148-155.
18. Corbett AD, Henderson G, McKnight AT, Paterson SJ, (2006). 75 years of opioid research: the exciting but vain quest for the holy grail. Br J Pharmacol 147 (Suppl. 1): S153-S162.
19. Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, et al. (2013). Constitutive mu-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science 341: 1394-1399.
20. Costa T, Herz A, (1989). Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins. Proc Natl Acad Sci U S A 86: 7321-7325.
21. Costantino CM, Gomes I, Stockton SD, Lim MP, Devi LA, (2012). Opioid receptor heteromers in analgesia. Expert Rev Mol Med 14: e9.
22. Cox BM, Christie MJ, Devi L, Toll L, Traynor JR, (2015). Challenges for opioid receptor nomenclature: IUPHAR Review 9. Br J Pharmacol 172: 317-323.
23. Davey AE, Leach K, Valant C, Conigrave AD, Sexton PM, Christopoulos A, (2012). Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology 153: 1232-1241.
24. De Lean A, Stadel JM, Lefkowitz RJ, (1980). A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem 255: 7108-7117.
25. Dewire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, et al. (2013). A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther 344: 708-717.
26. Ehlert FJ, (1988). Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Mol Pharmacol 33: 187-194.
27. Emmerson PJ, Clark MJ, Mansour A, Akil H, Woods JH, Medzihradsky F, (1996). Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the mu opioid receptor. J Pharmacol Exp Ther 278: 1121-1127.
28. Evans CJ, Keith DE Jr, Morrison H, Magendzo K, Edwards RH, (1992). Cloning of a delta opioid receptor by functional expression. Science 258: 1952-1955.
29. Evans T, Hepler JR, Masters SB, Brown JH, Harden TK, (1985). Guanine nucleotide regulation of agonist binding to muscarinic cholinergic receptors. Relation to efficacy of agonists for stimulation of phosphoinositide breakdown and Ca2 + mobilization. Biochem J 232: 751-757.
30. Gao ZG, Kim SK, Ijzerman AP, Jacobson KA, (2005). Allosteric modulation of the adenosine family of receptors. Mini Rev Med Chem 5: 545-553.
31. Gasparini F, Kuhn R, Pin JP, (2002). Allosteric modulators of group I metabotropic glutamate receptors: novel subtype-selective ligands and therapeutic perspectives. Curr Opin Pharmacol 2: 43-49.
32. Gjoni T, Urwyler S, (2008). Receptor activation involving positive allosteric modulation, unlike full agonism, does not result in GABAB receptor desensitization. Neuropharmacology 55: 1293-1299.
33. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA, (2004). A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci U S A 101: 5135-5139.
34. Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, et al. (2012). Structure of the delta-opioid receptor bound to naltrindole. Nature 485: 400-404.
35. Gupta A, Mulder J, Gomes I, Rozenfeld R, Bushlin I, Ong E, et al. (2010). Increased abundance of opioid receptor heteromers after chronic morphine administration. Sci Signal 3: ra54.
36. Hall DA, (2000). Modeling the functional effects of allosteric modulators at pharmacological receptors: an extension of the two-state model of receptor activation. Mol Pharmacol 58: 1412-1423.
37. Hegadoren KM, O'Donnell T, Lanius R, Coupland NJ, Lacaze-Masmonteil N, (2009). The role of beta-endorphin in the pathophysiology of major depression. Neuropeptides 43: 341-353.
38. Hendricson A, Matchett M, Ferrante M, Ferrante C, Hunnicutt E, Westphal R, et al. (2012). Design of an automated enhanced-throughput platform for functional characterization of positive allosteric modulator-induced leftward shifts in apparent agonist potency in vitro. J Lab Autom 17: 104-115.
39. Jager D, Schmalenbach C, Prilla S, Schrobang J, Kebig A, Sennwitz M, et al. (2007). Allosteric small molecules unveil a role of an extracellular E2/transmembrane helix 7 junction for G protein-coupled receptor activation. J Biol Chem 282: 34968-34976.
40. Janecka A, Fichna J, Janecki T, (2004). Opioid receptors and their ligands. Curr Top Med Chem 4: 1-17.
41. Juurlink DN, Dhalla IA, (2012). Dependence and addiction during chronic opioid therapy. J Med Toxicol 8: 393-399.
42. Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E, (2006). Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 372: 354-361.
43. Kenakin T, (2011). Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 336: 296-302.
44. Kenakin T, Christopoulos A, (2013). Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov 12: 205-216.
45. Keov P, Sexton PM, Christopoulos A, (2011). Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology 60: 24-35.
46. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG, (1992). The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci U S A 89: 12048-12052.
47. Koole C, Wootten D, Simms J, Valant C, Sridhar R, Woodman OL, et al. (2010). Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening. Mol Pharmacol 78: 456-465.
48. Lambert DG, (2008). The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 7: 694-710.
49. Langmead CJ, (2012). Ligand properties and behaviours in an allosteric age. Trends Pharmacol Sci 33: 621-622.
50. Leach K, Sexton PM, Christopoulos A, (2007). Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol Sci 28: 382-389.
51. Levine JD, Gordon NC, Jones RT, Fields HL, (1978). The narcotic antagonist naloxone enhances clinical pain. Nature 272: 826-827.
52. Lutz PE, Kieffer BL, (2013). Opioid receptors: distinct roles in mood disorders. Trends Neurosci 36: 195-206.
53. Mailman RB, (2007). GPCR functional selectivity has therapeutic impact. Trends Pharmacol Sci 28: 390-396.
54. Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, et al. (2012). Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485: 321-326.
55. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, et al. (1996). Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383: 819-823.
56. May LT, Leach K, Sexton PM, Christopoulos A, (2007). Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 47: 1-51.
57. McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, Chew PW, et al. (2003). Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 4: 231-256.
58. McPherson J, Rivero G, Baptist M, Llorente J, Al-Sabah S, Krasel C, et al. (2012). mu-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol Pharmacol 78: 756-766.
59. Melancon BJ, Hopkins CR, Wood MR, Emmitte KA, Niswender CM, Christopoulos A, et al. (2012). Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem 55: 1445-1464.
60. Melnikova I, (2010). Pain market. Nat Rev Drug Discov 9: 589-590.
61. Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, et al. (1995). Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377: 532-535.
62. Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, et al. (1994). ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 341: 33-38.
63. Monod J, Changeux JP, Jacob F, (1963). Allosteric proteins and cellular control systems. J Mol Biol 6: 306-329.
64. Monod J, Wyman J, Changeux JP, (1965). On the nature of allosteric transitions: a plausible model. J Mol Biol 12: 88-118.
65. Pradhan AA, Smith ML, Kieffer BL, Evans CJ, (2012). Ligand-directed signalling within the opioid receptor family. Br J Pharmacol 167: 960-969.
66. Przewlocki R, Przewlocka B, (2001). Opioids in chronic pain. Eur J Pharmacol 429: 79-91.
67. Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, et al. (1994). Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 45: 330-334.
68. Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, et al. (1995). Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270: 792-794.
69. Rivero G, Llorente J, McPherson J, Cooke A, Mundell SJ, McArdle CA, et al. (2010). Endomorphin-2: a biased agonist at the mu-opioid receptor. Mol Pharmacol 82: 178-188.
70. Rives ML, Rossillo M, Liu-Chen LY, Javitch JA, (2012). 6'-guanidinonaltrindole (6'-GNTI) is a G protein-biased kappa-opioid receptor agonist that inhibits arrestin recruitment. J Biol Chem 287: 27050-27054.
71. Roques BP, Fournie-Zaluski MC, Wurm M, (2012). Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nat Rev Drug Discov 11: 292-310.
72. Rothman RB, Murphy DL, Xu H, Godin JA, Dersch CM, Partilla JS, et al. (2007). Salvinorin A: allosteric interactions at the mu-opioid receptor. J Pharmacol Exp Ther 320: 801-810.
73. Sadee W, Wang D, Bilsky EJ, (2005). Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities. Life Sci 76: 1427-1437.
74. Samama P, Cotecchia S, Costa T, Lefkowitz RJ, (1993). A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem 268: 4625-4636.
75. Sheffler DJ, Roth BL, (2003). Salvinorin A: the 'magic mint' hallucinogen finds a molecular target in the kappa opioid receptor. Trends Pharmacol Sci 24: 107-109.
76. Snyder SH, Pasternak GW, (2003). Historical review: opioid receptors. Trends Pharmacol Sci 24: 198-205.
77. Stockton JM, Birdsall NJ, Burgen AS, Hulme EC, (1983). Modification of the binding properties of muscarinic receptors by gallamine. Mol Pharmacol 23: 551-557.
78. Stockton SD Jr, Devi LA, (2012). Functional relevance of mu-delta opioid receptor heteromerization: a role in novel signaling and implications for the treatment of addiction disorders: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend 121: 167-172.
79. Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, et al. (2012). Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485: 395-399.
80. Tota MR, Schimerlik MI, (1990). Partial agonist effects on the interaction between the atrial muscarinic receptor and the inhibitory guanine nucleotide-binding protein in a reconstituted system. Mol Pharmacol 37: 996-1004.
81. Vallejo R, Barkin RL, Wang VC, (2011). Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Physician 14: E343-E360.
82. Violin JD, Lefkowitz RJ, (2007). Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci 28: 416-422.
83. Waldhoer M, Bartlett SE, Whistler JL, (2004). Opioid receptors. Annu Rev Biochem 73: 953-990.
84. Way EL, Loh HH, Shen FH, (1969). Simultaneous quantitative assessment of morphine tolerance and physical dependence. J Pharmacol Exp Ther 167: 1-8.
85. Weiss JM, Morgan PH, Lutz MW, Kenakin TP, (1996). The cubic ternary complex receptor-occupancy model. III. resurrecting efficacy. J Theor Biol 181: 381-397.
86. Whalen EJ, Rajagopal S, Lefkowitz RJ, (2011). Therapeutic potential of beta-arrestin- and G protein-biased agonists. Trends Mol Med 17: 126-139.
87. Whistler JL, (2012). Examining the role of mu opioid receptor endocytosis in the beneficial and side-effects of prolonged opioid use: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend 121: 189-204.
88. Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, et al. (2013). Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65: 223-254.
89. Woodcock J, (2009). A difficult balance-pain management, drug safety, and the FDA. N Engl J Med 361: 2105-2107.
90. Wootten D, Savage EE, Valant C, May LT, Sloop KW, Ficorilli J, et al. (2012). Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol 82: 281-290.
91. Wootten D, Christopoulos A, Sexton PM, (2013). Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 12: 630-644.
92. Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, et al. (2012). Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485: 327-332.
93. Yasuda K, Raynor K, Kong H, Breder CD, Takeda J, Reisine T, et al. (1993). Cloning and functional comparison of kappa and delta opioid receptors from mouse brain. Proc Natl Acad Sci U S A 90: 6736-6740.
94. Zadina JE, Hackler L, Ge LJ, Kastin AJ, (1997). A potent and selective endogenous agonist for the mu-opiate receptor. Nature 386: 499-502.
95. Zhang L, Loh HH, Law PY, (2013). A novel noncanonical signaling pathway for the mu-opioid receptor. Mol Pharmacol 84: 844-853.