Identification of Opioid Ligands Possessing Mixed μ Agonist/δ Antagonist Activity among Pyridomorphinans Derived from Naloxone, Oxymorphone, and Hydropmorphone

Journal of Medicinal Chemistry

Volumn 47, Issue 6, 2004, Pages 1400-1412

  Ananthan, Subramaniam ^a   Khare, Naveen K ^a   Saini, Surendra K ^a   Seitz, Lainne E ^a   Bartlett, Jeffrey L ^d   Davis, Peg ^c   Dersch, Christina M ^b   Porreca, Frank ^c   Rothman, Richard B ^b   Bilsky, Edward J ^d  

^a SOUTHERN RESEARCH INSTITUTE   (United States)

^b NATIONAL INSTITUTE ON DRUG ABUSE   (United States)

^c UNIVERSITY OF ARIZONA   (United States)

^d UNIVERSITY OF NEW ENGLAND   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

17 ALLYL 6,7 DIDEHYDRO 3,14 DIHYDROXY 4,5ALPHA EPOXY 5' (4 CHLOROPHENYL)PYRIDO[2',3':6,7]MORPHINAN; 5' (3,4 DICHLOROPHENYL) 6,7 DIDEHYDRO 4,5ALPHA EPOXY 3 HYDROXY 17 METHYLPYRIDO[2',3':6,7]MORPHINAN; 5' (4 BROMOPHENYL) 6,7 DIDEHYDRO 3,14 DIHYDROXY 4,5ALPHA EPOXY 17 METHYLPYRIDO[2',3':6,7]MORPHINAN; 5' (4 BROMOPHENYL) 6,7 DIDEHYDRO 4,5ALPHA EPOXY 3 HYDROXY 17 METHYLPYRIDO[2',3':6,7]MORPHINAN; 5' (4 CHLOROPHENYL) 6,7 DIDEHYDRO 3,14 DIHYDROXY 4,5ALPHA EPOXY 17 METHYLPYRIDO[2',3':6,7]MORPHINAN; 5' (4 CHLOROPHENYL) 6,7 DIDEHYDRO 4,5ALPHA EPOXY 3 HYDROXY 17 METHYLPYRIDO[2',3':6,7]MORPHINAN; 6,7 DIDEHYDRO 3,14 DIHYDROXY 4,5ALPHA EPOXY 17 METHYL 5' PHENYLPYRIDO[2',3':6,7]MORPHINAN; 6,7 DIDEHYDRO 3,14 DIHYDROXY 4,5ALPHA EPOXY 17 METHYLPYRIDO[2',3':6,7]MORPHINAN; 6,7 DIDEHYDRO 4,5ALPHA EPOXY 3 HYDROXY 17 METHYL 5' PHENYLPYRIDO[2',3':6,7]MORPHINAN; 6,7 DIDEHYDRO 4,5ALPHA EPOXY 3 HYDROXY 17 METHYLPYRIDO[2',3':6,7]MORPHINAN; DELTA OPIATE RECEPTOR; DELTA OPIATE RECEPTOR ANTAGONIST; HYDROMORPHONE; KAPPA OPIATE RECEPTOR; MORPHINAN DERIVATIVE; MU OPIATE RECEPTOR; MU OPIATE RECEPTOR AGONIST; NALOXONE; OPIATE; OXYMORPHONE; PYRIDOMORPHINAN DERIVATIVE; UNCLASSIFIED DRUG;

ANALGESIC ACTIVITY; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINOCICEPTION; ARTICLE; BINDING AFFINITY; BINDING SITE; BRAIN MEMBRANE; BRAIN TISSUE; CONTROLLED STUDY; DOSE RESPONSE; DRUG IDENTIFICATION; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERANCE; GUINEA PIG; ILEUM; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; SMOOTH MUSCLE; STRUCTURE ANALYSIS; VAS DEFERENS;

ANALGESICS; ANIMALS; BINDING SITES; BRAIN; DRUG TOLERANCE; ELECTRIC STIMULATION; GUINEA PIGS; HYDROMORPHONE; ILEUM; LIGANDS; MALE; MICE; MICE, INBRED ICR; MORPHINANS; MUSCLE CONTRACTION; MUSCLE, SMOOTH; NALOXONE; OXYMORPHONE; PYRIDINES; RADIOLIGAND ASSAY; RATS; RECEPTORS, OPIOID, DELTA; RECEPTORS, OPIOID, MU; VAS DEFERENS;

EID: 12144289451     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm030311v     Document Type: Article

References (45)

1. Parrott, T. Using Opioid Analgesics To Manage Chronic Non-cancer Pain in Primary Care. J. Am. Board Fam. Pract. 1999, 12, 293-306.
2. Cherny, N. New Strategies in Opioid Therapy for Cancer Pain. J. Oncol. Manage. 2000, 9, 8-15.
3. Dhawan, B. N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley, P. B.; Portoghese, P. S.; Hamon, M. International Union of Pharmacology. XII Classification of Opioid Receptors. Pharmacol. Rev. 1996, 48, 567-592.
4. Aldrich, J. V.; Vigil-Cruz, S. C. Narcotic Analgesics. In Burger's Medicinal Chemistry and Drug Discovery, Abraham, D. J., Ed.; John Wiley & Sons: New York, 2003; Vol. 6, pp 329-481.
5. Duthie, D. J.; Nimmo, W. S. Adverse Effects of Opioid Analgesic Drugs. Br. J. Anaesth. 1987, 59, 61-77.
6. van Ree, J. M.; Gerrits, M. A.; Vanderschuren, L. J. Opioids, Reward and Addiction: An Encounter of Biology, Psychology, and Medicine. Pharmacol. Rev. 1999, 51, 341-396.
7. Traynor, J. R.; Elliott, J. δ-Opioid Receptor Subtypes and Cross-Talk with μ-Receptors. Trends Pharmacol. Sci. 1993, 14, 84-86.
8. Rothman, R. B.; Holaday, J. W.; Porreca, F. Allosteric Coupling among Opioid Receptors: Evidence for an Opioid Receptor Complex. In Opioids I; Herz, A., Akil, H., Simon, E. J., Eds; Handbook of Experimental Pharmacology, Volume 104; Springer-Verlag: Berlin, 1993; pp 217-237.
9. Jordan, B. A.; Devi, L. A. G-Protein-Coupled Receptor Heterodimerization Modulates Receptor Function. Nature 1999, 399, 697-700.
10. George, S. R.; Fan, T.; Xie, Z.; Tse, R.; Tam, V.; Varghese, G.; O'Dowd, B. F. Oligomerization of μ- and δ-Opioid Receptors. J. Biol. Chem. 2000, 275, 26128-26135.
11. Levac, B. A. R.; O'Dowd, B. F.; George, S. R. Oligomerization of Opioid Receptors: Generation of Novel Signaling Units. Curr. Opin. Pharmacol. 2002, 2, 76-81.
12. Abdelhamid, E. E.; Sultana, M.; Portoghese, P. S.; Takemori, A. E. Selective Blockage of Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependence in Mice. J. Pharmacol. Exp. Ther. 1991, 258, 299-303.
13. Fundytus, M. E.; Schiller, P. W.; Shapiro, M.; Weltrowska, G.; Coderre, T. J. Attenuation of Morphine Tolerance and Dependence with the Highly Selective δ-Opioid Receptor Antagonist TIPP[Ψ]. Eur. J. Pharmacol. 1995, 286, 105-108.
14. Schiller, P. W.; Weltrowska, G.; Schmidt, R.; Nguyen, T. M.-D.; Berezowska, I.; Lemieux, C.; Chung, N. N.; Carpenter, K. A.; Wilkes, B. C. Four Different Types of Opioid Peptides with Mixed μ Agonist/δ Antagonist Properties. Analgesia 1995, 1, 703-706.
15. 2[Ψ] Produces a Potent Analgesic Effect, No Physical Dependence, and Less Tolerance Than Morphine in Rats. J. Med. Chem. 1999, 42, 3520-3526.
16. Suzuki, T.; Ikeda, H.; Tsuji, M.; Misawa, M.; Narita, M.; Tseng, L. F. Antisense Oligodeoxynucleotide to δ Opioid Receptors Attenuates Morphine Dependence in Mice. Life Sci. 1997, 61, 165-170.
17. Sanchez-Blazquez, P.; Garcia-Espana, A.; Garzon, J. Antisense Oligodeoxynucleotides to Opioid Mu and Delta Receptors Reduced Morphine Dependence in Mice: Role of Delta-2 Opioid Receptors. J. Pharmacol. Exp. Ther. 1997, 280, 1423-1431.
18. Zhu, Y.; King, M. A.; Schuller, A. G. P.; Nitsche, J. F.; Reidl, M.; Elde, R. P.; Unterwald, E.; Pasternak, G. W.; Pintar, J. E. Retention of Supraspinal Delta-like Analgesia and Loss of Morphine Tolerance in δ Opioid Receptor Knockout Mice. Neuron 1999, 24, 243-252.
19. Ananthan, S.; Kezar, H. S., III; Carter, R. L.; Saini, S. K.; Rice, K. C.; Wells, J. L.; Davis, P.; Xu, H.; Dersch, C. M.; Bilsky, E. J.; Porreca, F.; Rothman, R. B. Synthesis, Opioid Receptor Binding, and Biological Activities of Naltrexone-Derived Pyrido-and Pyrimidomorphinans. J. Med. Chem. 1999, 42, 3527-3538.
20. Ananthan, S.; Kezar, H. S., III; Saini, S. K.; Khare, N. K.; Davis, P.; Dersch, C. M.; Porreca, F.; Rothman, R. B. Synthesis, Opioid Receptor Binding, and Functional Activity of 5′-Substituted 17-Cyclopropylmethylpyrido [2′,3′:6,7]morphinans. Bioorg. Med. Chem. Lett. 2003, 13, 529-532.
21. Wells, J. L.; Bartlett, J. L.; Ananthan, S.; Bilsky, E. J. In Vivo Pharmacological Characterization of SoRI 9409, a Nonpeptidic Opioid/μ Agonist/δ-Antagonist That Produces Limited Antinociceptive Tolerance and Attenuates Morphine Physical Dependence. J. Pharmacol. Exp. Ther. 2001, 297, 597-605.
22. 35S]-GTP-γ-S Binding at Cloned Opioid Receptors. Brain Res. Bull. 2001, 55, 507-511.
23. Ananthan, S.; Khare, N. K.; Saini, S. K.; Davis, P.; Dersch, C. M.; Porreca, F.; Rothman, R. B. Novel Ligands for the Opioid Receptors: Synthesis and Structure-Activity Relationships among 5′-Aryl and 5′-Heteroaryl 17-Cyclopropylmethyl-4,5α.-epoxypyrido[2′ ,3′:6,7]morphinans. Bioorg. Med. Chem. 2003, 11, 4143-4154.
24. Casy, A. F.; Partfitt, R. T. Opioid Analgesics: Chemistry and Receptors; Plenum Press: New York, 1986.
25. Lenz, G. R.; Evans, S. M.; Walters, D. E.; Hopfinger, A. J. Opiates; Academic Press: Orlando, FL, 1986.
26. Maguire, P. A.; Perez, J. J.; Tsai, N. F.; Rodriguez, L.; Beatty, M. F.; Villar, H. O.; Kamal, J. J.; Upton, C.; Casy, A. F.; Loew, G. H. Molecular Mechanism of δ-Selectivity of Indole Analogs of Nonpeptide Opioids. Mol. Pharmacol. 1993, 44, 1246-1251.
27. Portoghese, P. S.; Larson, D. L.; Sultana, M.; Takemori, A. E. Opioid Agonist and Antagonist Activities of Morphindoles Related to Naltrindole. J. Med. Chem. 1992, 35, 4325-4329.
28. McLamore, S.; Ullrich, T.; Rothman, R. B.; Xu, H.; Dersch, C.; Coop, A.; Davis, P.; Porreca, F.; Jacobson, A. E.; Rice, K. C. Effect of N-Alkyl and N-Alkenyl Substituents in Noroxyrnorphindole, 17-Substituted-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7:2′, 3′-indolomorphinans, on Opioid Receptor Affinity, Selectivity, and Efficacy. J. Med. Chem. 2001, 44, 1471-1474.
29. Kshirsagar, T. A.; Fang, X.; Portoghese, P. S. 14-Desoxy Analogues of Naltrindole and 7-Spiroindanyloxymorphone: The Role of the 14-Hydroxy Group at δ Opioid Receptors. J. Med. Chem. 1998, 41, 2657-2660.
30. 5-Enkephalin Binding Site. Neuropeptides 1988, 11, 13-16.
31. Rothman, R. B.; Xu, H.; Seggel, M.; Jacobson, A. E.; Rice, K. C.; Brine, G. A.; Carroll, F. I. RTI-4614-4: An Analog of (+)-cis-3-Methylfentanyl with a 27,000-Fold Binding Selectivity for Mu Versus Delta Opioid Binding Sites. Life Sci. 1991, 48, 111-116.
32. Rothman, R. B.; Bykov, V.; de Costa, B. R.; Jacobson, A. E.; Rice, K. C. ; Brady, L. S. Interaction of Endogenous Opioid Peptides and Other Drugs with Four Kappa Opioid Binding Sites in Guinea Pig Brain. Peptides 1990, 11, 311-331.
33. Ananthan, S.; Johnson, C. A.; Carter, R. L.; Clayton, S. D.; Rice, K. C. ; Xu, H.; Davis, P.; Porreca, F.; Rothman, R. B. Synthesis, Opioid Receptor Binding, and Bioassay of Naltrindole Analogues Substituted in the Indolic Benzene Moiety. J. Med. Chem. 1998, 41, 2872-2881.
34. Thomas, J. B.; Atkinson, R. N.; Herault, X. M.; Rothman, R. B.; Mascarella, S. W.; Dersch, C. M.; Xu, H.; Horel, R. B.; Carroll, F. I. Optically Pure (-)-4-[(N-Allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide Displays Selective Binding and Full Agonist Activity for the δ Opioid Receptor. Bioorg. Med. Chem. Lett. 1999, 9, 3347-3350.
35. Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Rothman, R. B.; Mascarella, S. W.; Xu, H.; Partilla, J. S.; Dersch, C. M.; McCullough, K. B.; Cantrell, B. E. ; Zimmerman, D. M.; Carroll, F. I. Identification of an Opioid κ Receptor Subtype-Selective N-Substituent for (+)-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine. J. Med. Chem. 1998, 41, 5188-5197.
36. 35S]GTP-γ-S Binding Assay. Analgesia 1999, 4, 27-32.
37. Kramer, T. H.; Davis, P.; Hruby, V. J.; Burks, T. F.; Porreca, F. In vitro Potency, Affinity and Agonist Efficacy of Highly Selective Delta Opioid Receptor Ligands. J. Pharmacol. Exp. Ther. 1993, 266, 577-584.
38. Porreca, F.; LoPresti, D.; Ward, S. J. Opioid Agonist Affinity in the Guinea-Pig Ileum and Mouse Vas Deferens. Eur. J. Pharmacol. 1990, 179, 129-139.
39. 35S]GTP-γ-S Functional Binding Assay. Synapse 2001, 39, 64-69.
40. Coppola, G. M.; Hardtmann, G. E.; Huegi, B. S. Synthesis and Reactions of 2-Aryl-3-(dimethylamino)acroleins. J. Heterocycl. Chem. 1974, 11, 51-56.
41. Stacey, G. J.; Hawkins, A. F.; Pearson, D. P. J.; Sunley, R. L. Pyridine Derivatives Inducing Tillering and Agricultural Compositions Containing Them. Eur. Pat. Appl. 67511, 1982; Chem. Abstr. 1983, 98, 198028.
42. Biziere, K.; Chambon, J. P.; Hallot, A. Heterocyclic Nitrogen Compounds. Eur. Pat. Appl. 169139, 1986; Chem. Abstr. 1986, 105, 97319.
43. Rodbard, D.; Lenox, R. H.; Wray, H. L.; Ramseth, D. Statistical Characterization of the Random Errors in the Radioimmunoassay Dose-Response Variable. Clin. Chem. 1976, 22, 350-358.
44. MINSQ Least Squares Parameter Estimation, version 3.05; MicroMath Inc.: St. Louis, MO, 1999.
45. Bilsky, E. J.; Inturrisi, C. E.; Sadee, W.; Hruby, V. J.; Porreca, F. Competitive and Non-Competitive NMDA Antagonists Block the Development of Antinociceptive Tolerance to Morphine, but Not to Selective μ or δ Opioid Agonists in Mice. Pain 1996, 68, 229-237.