Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB 1) receptors are potent analgesics devoid of tolerance

Journal of Medicinal Chemistry

Volumn 56, Issue 13, 2013, Pages 5505-5513

  Le Naour, Morgan ^a   Akgün, Eyup ^a   Yekkirala, Ajay ^a   Lunzer, Mary M ^a   Powers, Mike D ^a   Kalyuzhny, Alexander E ^b   Portoghese, Philip S ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

^b UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANNABINOID 1 RECEPTOR; MU OPIATE RECEPTOR;

ANTINOCICEPTION; ARTICLE; DRUG DOSE; DRUG TOLERANCE; ENDOCYTOSIS; HUMAN; HUMAN CELL; IN VIVO STUDY; INTERNALIZATION; LATENT PERIOD; MALE; MORPHINE TOLERANCE; NOCICEPTION; NONHUMAN; PHARMACOPHORE; STRUCTURE ACTIVITY RELATION;

ANALGESICS, OPIOID; ANIMALS; CELL MEMBRANE; DRUG DESIGN; DRUG TOLERANCE; ENDOCYTOSIS; FLUORESCENT ANTIBODY TECHNIQUE; HEK293 CELLS; HUMANS; INJECTIONS, INTRAVENTRICULAR; INJECTIONS, SPINAL; LIGANDS; MALE; MICE, INBRED ICR; MODELS, CHEMICAL; MOLECULAR STRUCTURE; PAIN; RECEPTOR, CANNABINOID, CB1; RECEPTORS, OPIOID, MU; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84880174862     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4005219     Document Type: Article

References (55)

1. Vigano, D.; Rubino, T.; Parolaro, D. Molecular and cellular basis of cannabinoid and opioid interactions Pharmacol., Biochem. Behav. 2005, 81, 360-368
2. Mansour, A.; Khachaturian, H.; Lewis, M.; Akil, H.; Watson, S. J. Anatomy of CNS opioid receptors Trends Neurosci. 1988, 11, 308-314 (two plates)
3. Herkenham, M.; Lynn, A. B.; Johnson, M. R.; Melvin, L. S.; De, C. B. R.; Rice, K. C. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study J. Neurosci. 1991, 11, 563-583
4. Rodriguez, J. J.; Mackie, K.; Pickel, V. M. Ultrastructural localization of the CB1 cannabinoid receptor in μ-opioid receptor patches of the rat caudate putamen nucleus J. Neurosci. 2001, 21, 823-833
5. Parolaro, D.; Rubino, T.; Vigano, D.; Massi, P.; Guidali, C.; Realini, N. Cellular mechanisms underlying the interaction between cannabinoid and opioid system Curr. Drug Targets 2010, 11, 393-405
6. Childers, S. R. Opioid receptor-coupled second messenger systems Life Sci. 1991, 48, 1991-2003
7. Howlett, A. C. Pharmacology of cannabinoid receptors Annu. Rev. Pharmacol. Toxicol. 1995, 35, 607-634
8. Childers, S. R.; Fleming, L.; Konkoy, C.; Marckel, D. O. N.; Pacheco, M.; Sexton, T.; Ward, S. Opioid and cannabinoid receptor inhibition of adenylyl cyclase in brain Ann. N.Y. Acad. Sci. 1992, 654, 33-51
9. Lichtman, A. H.; Cook, S. A.; Martin, B. R. Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement J. Pharmacol. Exp. Ther. 1996, 276, 585-593
10. Arvidsson, U.; Riedl, M.; Chakrabarti, S.; Lee, J.-H.; Nakano, A. H.; Dado, R. J.; Loh, H. H.; Law, P.-Y.; Wessendorf, M. W.; Elde, R. Distribution and targeting of a μ-opioid receptor (MOR1) in brain and spinal cord J. Neurosci. 1995, 15, 3328-3341
11. Desroches, J.; Beaulieu, P. Opioids and cannabinoids interactions: involvement in pain management Curr. Drug Targets 2010, 11, 462-473
12. Cichewicz, D. L.; Martin, Z. L.; Smith, F. L.; Welch, S. P. Enhancement of μ opioid antinociception by oral Δ9-tetrahydrocannabinol: dose-response analysis and receptor identification J. Pharmacol. Exp. Ther. 1999, 289, 859-867
13. Reche, I.; Fuentes, J. A.; Ruiz-Gayo, M. Potentiation of Δ9-tetrahydrocannabinol-induced analgesia by morphine in mice: involvement of μ- and κ-opioid receptors Eur. J. Pharmacol. 1996, 318, 11-16
14. Cichewicz, D. L.; Welch, S. P. Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated withdrawal signs by oral Δ9-tetrahydrocannabinol J. Pharmacol. Exp. Ther. 2003, 305, 812-817
15. Cichewicz, D. L.; McCarthy, E. A. Antinociceptive synergy between Δ9-tetrahydrocannabinol and opioids after oral administration J. Pharmacol. Exp. Ther. 2003, 304, 1010-1015
16. Williams, J.; Haller, V. L.; Stevens, D. L.; Welch, S. P. Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception Eur. J. Pharmacol. 2008, 584, 78-86
17. Roberts, J. D.; Gennings, C.; Shih, M. Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine Eur. J. Pharmacol. 2006, 530, 54-58
18. Tham, S. M.; Angus, J. A.; Tudor, E. M.; Wright, C. E. Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2-adrenoceptor agonists in acute pain models in mice Br. J. Pharmacol. 2005, 144, 875-884
19. Trang, T.; Sutak, M.; Jhamandas, K. Involvement of cannabinoid (CB1)-receptors in the development and maintenance of opioid tolerance Neuroscience (San Diego, CA, U. S.) 2007, 146, 1275-1288
20. Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.; Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Neliat, G.; Caput, D.; Ferrara, P.; Soubrie, P.; Breliere, J. C.; Le Fur, G. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor FEBS Lett. 1994, 350, 240-244
21. Mas-Nieto, M.; Pommier, B.; Tzavara, E. T.; Caneparo, A.; Da, N. S.; Le, F. G.; Roques, B. P.; Noble, F. Reduction of opioid dependence by the CB1 antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction Br. J. Pharmacol. 2001, 132, 1809-1816
22. Navarro, M.; Carrera, M. R. A.; Fratta, W.; Valverde, O.; Cossu, G.; Fattore, L.; Chowen, J. A.; Gomez, R.; Del, A. I.; Villanua, M. A.; Maldonado, R.; Koob, G. F.; Rodriguez de Fonseca, F. Functional interaction between opioid and cannabinoid receptors in drug self-administration J. Neurosci. 2001, 21, 5344-5350
23. Cossu, G.; Ledent, C.; Fattore, L.; Imperato, A.; Bohme, G. A.; Parmentier, M.; Fratta, W. Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse Behav. Brain Res. 2001, 118, 61-65
24. Castane, A.; Robledo, P.; Matifas, A.; Kieffer, B. L.; Maldonado, R. Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice Eur. J. Neurosci. 2003, 17, 155-159
25. Hojo, M.; Sudo, Y.; Ando, Y.; Minami, K.; Takada, M.; Matsubara, T.; Kanaide, M.; Taniyama, K.; Sumikawa, K.; Uezono, Y. μ-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis J. Pharmacol. Sci. (Tokyo, Jpn.) 2008, 108, 308-319
26. Rios, C.; Gomes, I.; Devi, L. A. μ opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis Br. J. Pharmacol. 2006, 148, 387-395
27. Pickel, V. M.; Chan, J.; Kash, T. L.; Rodriguez, J. J.; MacKie, K. Compartment-specific localization of cannabinoid 1 (CB1) and μ-opioid receptors in rat nucleus accumbens Neuroscience (Oxford, U. K.) 2004, 127, 101-112
28. 1-cannabinoid and μ-opioid receptor colocalization on postsynaptic target in the rat dorsal horn NeuroReport 2001, 12, 3689-3692
29. Lenard, N. R.; Daniels, D. J.; Portoghese, P. S.; Roerig, S. C. Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores Eur. J. Pharmacol. 2007, 566, 75-82
30. Bhushan, R. G.; Sharma, S. K.; Xie, Z.; Daniels, D. J.; Portoghese, P. S. A bivalent ligand (KDN-21) reveals spinal δ and κ opioid receptors are organized as heterodimers that give rise to δ1 and κ2 phenotypes. Selective targeting of δ-κ heterodimers J. Med. Chem. 2004, 47, 2969-2972
31. Portoghese, P. S.; Larson, D. L.; Sayre, L. M.; Yim, C. B.; Ronsisvalle, G.; Tam, S. W.; Takemori, A. E. Opioid agonist and antagonist bivalent ligands. The relationship between spacer length and selectivity at multiple opioid receptors J. Med. Chem. 1986, 29, 1855-1861
32. Portoghese, P. S.; Larson, D. L.; Yim, C. B.; Sayre, L. M.; Ronsisvalle, G.; Lipkowski, A. W.; Takemori, A. E.; Rice, K. C.; Tam, S. W. Stereostructure-activity relationship of opioid agonist and antagonist bivalent ligands. Evidence for bridging between vicinal opioid receptors J. Med. Chem. 1985, 28, 1140-1141
33. Daniels, D. J.; Kulkarni, A.; Xie, Z.; Bhushan, R. G.; Portoghese, P. S. A bivalent ligand (KDAN-18) containing delta-antagonist and kappa-agonist pharmacophores bridges delta2 and kappa1 opioid receptor phenotypes J. Med. Chem. 2005, 48, 1713-1716
34. Akgün, E.; Javed, M. I.; Lunzer, M. M.; Smeester, B. A.; Beitz, A. J.; Portoghese, P. S. Opioid mu agonist/mGluR5 antagonist bivalent ligands produce potent antinociception in mice with inflammatory pain. Proc. Natl. Acad. Sci. U.S.A. 2013, in press.
35. Harikumar, K. G.; Akgun, E.; Portoghese, P. S; Miller, L. J. Induced association of micro opioid (MOP) and type 2 cholecystokinin (CCK2) receptors by novel bivalent ligands J. Med. Chem. 2010, 53, 2836-2842
36. Daniels, D. J.; Lenard, N. R.; Etienne, C. L.; Law, P.-Y.; Roerig, S. C.; Portoghese, P. S. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 19208-19213
37. Metzger, T. G.; Paterlini, M. G.; Ferguson, D. M.; Portoghese, P. S. Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the "address" recognition locus J. Med. Chem. 2001, 44, 857-862
38. Caille, S.; Parsons, L. H. Cannabinoid modulation of opiate reinforcement through the ventral striatopallidal pathway Neuropsychopharmacology 2006, 31, 804-813
39. Azizi, P.; Haghparast, A.; Hassanpour-Ezatti, M. Effects of CB1 receptor antagonist within the nucleus accumbens on the acquisition and expression of morphine-induced conditioned place preference in morphine-sensitized rats Behav. Brain Res. 2009, 197, 119-124
40. Portoghese, P. S. Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists Trends Pharmacol. Sci. 1989, 10, 230-235
41. Portoghese, P. S. From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes J. Med. Chem. 2001, 44, 2259-2269
42. Portoghese, P. S.; Ronsisvalle, G.; Larson, D. L.; Takemori, A. E. Synthesis and opioid antagonist potencies of naltrexamine bivalent ligands with conformationally restricted spacers J. Med. Chem. 1986, 29, 1650-1653
43. Portoghese, P. S.; Ronsisvalle, G.; Larson, D. L.; Yim, C. B.; Sayre, L. M.; Takemori, A. E. Opioid agonist and antagonist bivalent ligands as receptor probes Life Sci. 1982, 31, 1283-1286
44. 1 receptor antagonist N -(piperidinyl)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide (SR141716) J. Med. Chem. 2002, 45, 2708-2719
45. Lange, J. H. M.; Kruse, C. G. Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists Drug Discovery Today 2005, 10, 693-702
46. Jagerovic, N.; Fernandez-Fernandez, C.; Goya, P. CB1 cannabinoid antagonists: structure activity relationships and potential therapeutic applications Curr. Top. Med. Chem. 2008, 8, 205-230
47. Seltzman, H. H.; Carroll, F. I.; Burgess, J. P.; Wyrick, C. D.; Burch, D. F. Tritiation of SR141716 by metalation-iodination-reduction: tritium-proton NOE study J. Labelled Compd. Radiopharm. 2002, 45, 59-70
48. Daniels, D. J. Bivalent Ligands as Probes for the Investigation of Opioid Receptor Dimerization. Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2006.
49. Yekkirala, A. S. Elucidation the Role of Opioid Receptor Heteromers as Targets for Analgesic Drug Design. Ph.D. Thesis, University of Minnesota, Minneapolis, MN 2011.
50. Yekkirala, A. S.; Kalyuzhny, A. E.; Portoghese, P. S. An immunocytochemical-derived correlate for evaluating the bridging of heteromeric mu-delta opioid protomers by bivalent ligands, ACS Chem. Biol. [Online early access]. DOI: 0.1021/cb400113d. Published Online: May 15, 2013.
51. Zheng, Y.; Akgun, E.; Harikumar, K. G.; Hopson, J.; Powers, M. D.; Lunzer, M. M.; Miller, L. J.; Portoghese, P. S. Induced association of μ opioid (MOP) and type 2 cholecystokinin (CCK2) receptors by novel bivalent ligands J. Med. Chem. 2009, 52, 247-258
52. Portoghese, P. S.; Lunzer, M. M. Identity of the putative delta 1-opioid receptor as a delta-kappa heteromer in the mouse spinal cord Eur. J. Pharmacol. 2003, 467, 233-234
53. D'Amour, F. E.; Smith, D. L. A method for determining loss of pain sensation J. Pharmacol. Exp. Ther. 1941, 72, 74-79
54. Dewey, W. L.; Harris, L. S.; Howes, J. F.; Nuite, J. A. Effect of various neurohumoral modulators on the activity of morphine and the narcotic antagonists in the tail-flick and phenylquinone tests J. Pharmacol. Exp. Ther. 1970, 175, 435-442
55. Harris, L. S.; Pierson, A. K. Narcotic antagonists in the benzomorphan series J. Pharmacol. Exp. Ther. 1964, 143, 141-148