Derivatives of tramadol for increased duration of effect

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 3, 2006, Pages 691-694

  Shao, Liming ^a   Abolin, Craig ^a   Hewitt, Michael C ^a   Koch, Patrick ^a   Varney, Mark ^a  

^a SUNOVION PHARMACEUTICALS INC   (United States)

Author keywords

Deuterium isotope effect; Metabolic stability; Opioids; Tramadol

Indexed keywords

ANALGESIC AGENT; CODEINE; DEUTERIUM; DRUG METABOLITE; HYDROGEN; MORPHINE; OPIATE; TRAMADOL;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DEUTERIUM HYDROGEN EXCHANGE; DRUG EFFECT; DRUG SCREENING; DRUG SYNTHESIS; HUMAN; HUMAN TISSUE; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; RAT;

ANALGESICS, OPIOID; ANIMALS; BINDING SITES; CODEINE; MODELS, CHEMICAL; MORPHINE; PAIN; RATS; TIME FACTORS; TRAMADOL;

ANIMALIA;

EID: 29544450417     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.10.024     Document Type: Article

References (24)

1. R.B. Raffa, E. Friderichs, W. Reimann, R.P. Shank, E.E. Good, and J.L. Vaught J. Pharmacol. Exp. Ther. 260 1992 275
2. T.P. Gibson Am. J. Med. 101 Suppl 1A 1996 47S
3. L. Radbruch, S. Grond, and K. Lehmann Drug Safety 15 1996 8
4. R.B. Raffa Am. J. Med. 101 Suppl 1A 1996 41S
5. M. Garrido, M. Valle, M.A. Campanero, R. Calvo, and I.F. Troconiz J. Pharmacol. Exp. Ther. 295 2000 352
6. V. Subrahmanyam, A.B. Renwick, D.G. Walters, P.J. Young, R.J. Price, A.P. Tonelli, and B.G. Lake Drug Metab. Dispos. 29 2001 1146
7. W.N. Wu, L.A. McKown, and S. Liao Xenobiotica 32 2002 411
8. W. Leppert, and J. Luczak Support Care Cancer 13 2005 5
9. Duhmke, R. M.; Cornblath, D. D.; Hollingshead, J. R. Cochrane Database Syst. Rev. 2004, 2, CD003726.
10. S. Grond, and A. Sablotzki Clin. Pharmacol. Ther. 43 2004 879
11. U. Klotz Arzneim.-Forsch. 53 2003 681
12. PDR Electronic Library, Thomson Scientific, http://www.thomsonhc.com/ pdrel/librarian, reference for Ultram® tablets (Ortho-McNeil).
13. R.B. Raffa, R.K. Nayak, S. Liao, and F.L. Minn Rev. Contemp. Pharmacother. 6 1995 485
14. K.B. Wilberg Chem. Rev. 55 1955 713
15. F.H. Westheimer Chem. Rev. 61 1961 265
16. C.J. Parli, and R.E. McMahon Drug Metab. Dispos. 1 1973 337
17. M. Tanabe, D. Yasuda, S. LeValley, and C. Mitoma Life Sci. 8 1969 1123
18. C. Elison, H. Rapoport, R. Laursen, and H.W. Elliott Science 134 1961 1078
19. f = 0.43.
20. f = 0.23.
21. R.W. Draper, D. Hou, R. Iyer, G.M. Lee, J.T. Liang, J.L. Mas, and E.J. Vater Org. Process Res. Dev. 2 1998 186
22. f = 0.45.
23. 2 (3 mM), and EDTA (1 mM). Reactions were started by the addition of the NADPH-generating system. At designated times (0, 90, and 180 min), a 500-μL aliquot was removed from the incubation and added to 500 μL acetonitrile to terminate the reaction. The amount of unchanged test compound was quantified by LC/MS/MS. Where appropriate, the amount of O-desmethyl metabolite formed was also assessed by LC/MS/MS.
24. General procedure for in vitro stability assay in human hepatocytes. Test compounds (23 μM) were incubated separately with a pool (n = 2) of cryopreserved human hepatocytes (2 million cells/mL) in Waymouth's+ (Waymouth's medium [without phenol red] supplemented with FBS (4.5%), insulin (5.6 μg/mL), glutamine (3.6 mM), sodium pyruvate (4.5 mM), and dexamethasone (0.9 μM)) at the final concentrations indicated. Each test article was added to incubations in 2.5 μL (1%) of methanol. Reactions were started when placed in the incubator. At designated times (0, 180, and 360 min), a 250-μL aliquot was removed from the incubation and added to 250 μL acetonitrile to terminate the reaction. Precipitated protein was removed by centrifugation (920g for 10 min at 10°C). Amount of unchanged parent compound was quantified as follows; an aliquot (20 μL) of the supernatant fraction was transferred to 1 mL of internal standard (50 ng/mL dextrorphan in 1:1 methanol/water, 51-fold dilution) and analyzed by LC/MS/MS. Additional incubations were performed with hepatocytes in which the test article was replaced with 7-ethoxycoumarin (500 μM, marker substrate) to determine if the hepatocytes were metabolically competent.