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DOI: 10.1039/A903325D (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 1, 1999, 2725-2733

Synthesis and serotonergic activity of 2-oxadiazolyl-5-substituted-N,N-dimethyltryptamines: novel antagonists for the vascular 5-HT1B-like receptor

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Gerard P. Moloney, Graeme R. Martin, Neil Mathews, Steve MacLennan, Susan Dodsworth, Pang Yih Sang, Cameron Knight, Miles Maxwell and Robert C. Glen

Abstract

The synthesis and vascular 5-HT1B-like receptor activity of a novel series of 2-oxadiazolyl-5-substituted tryptamine derivatives 2 is described. Modifications to the 2-oxadiazolyl group R1, the heterocycle R2 and the length of the linking chain (n) have been explored. Several compounds were identified which exhibited moderate 5-HT1B-like receptor affinity. In particular, 2-(3-ethyl-1,2,4-oxadiazol-5-yl)-3-[2-(dimethylamino)ethyl]-5-[(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)methyl]-1H-indole (20) in which n = 1 had a pKB = 7.23 at the 5-HT1B-like receptor and >60 fold selectivity over α1-adrenoceptor affinity. This contrasts with the higher homologue derivatives such as 10 and 11 where n = 2 which exhibited decreased potency and selectivity for the 5-HT1B-like receptor. The 2-oxadiazolyl-5-substituted-N,N-dimethyltryptamine derivatives were found to be silent (as judged by the inability of angiotensin II to unmask 5-HT1B-like receptor mediated agonist activity in the rabbit femoral artery) and competitive 5-HT1B-like receptor antagonists with half lives of up to 1.5 hours in dog plasma and with good oral bioavailability.

References

  1. C. Gluchowski, T. A. Branchek, R. L. Weinshank and P. R. Hartig, Annu. Rep. Med. Chem., 1993, 28, 29 Search PubMed.
  2. P. R. Hartig, P. P. A. Adham, J. Zgombic, R. L. Weinshank and T. A. Branchek, Drug. Dev. Res., 1992, 26, 215 CAS.
  3. G. R. Martin and P. P. A. Humphrey, Neuropharmacology, 1994, 33, 261 CrossRef CAS.
  4. D. Hoyer, D. E. Clark and J. R. Fozard, Pharmacol. Rev., 1994, 46, 157 Search PubMed.
  5. E. Zifa and G. Fillion, Pharmacol. Rev., 1992, 44, 401 Search PubMed.
  6. 5-HT1D Receptor: a progress review, Neurochem. Res., 1990, 15, 573 Search PubMed.
  7. P. R. Hartig, D. Hoyer, P. P. A. Humphrey and G. R. Martin, Trends. Pharmacol. Sci., 1996, 17, 103 CrossRef CAS.
  8. P. P. A. Humphrey, W. Feniuk, M. J. Perren, H. E. Connor, A. W. Oxford, I. H. Coates and D. Butina, Br. J. Pharmacol., 1988, 94, 1123 CAS.
  9. K. L. Dechant and S. P. Clissold, Drugs, 1992, 43, 776 Search PubMed.
  10. P. C. North, Migraine Therapy—Serotonin to Sumatriptan in Medicinal Chemistry: Principles and Practice, ed. F. G. King, The Royal Society of Chemistry, 1994 Search PubMed.
  11. R. C. Glen, A. P. Hill, G. R. Martin and A. D. Robertson, Headache, 1994, 34, 307 Search PubMed.
  12. R. C. Glen, G. R. Martin, A. P. Hill, R. M. Hyde, P. M. Woolard, J. A. Salmon, J. Buckingham and A. D. Robertson, J. Med. Chem., 1995, 38, 3566 CrossRef CAS.
  13. L. J. Street, R. Baker, J. L. Castro, M. S. Chambers, A. R. Guiblin, S. C. Hobbs, V. G. Matassa, A. J. Reeve, M. S. Beer, D. N. Middlemiss, A. J. Noble, J. A. Stanton, K. Scholey and R. J. Hargreaves, J. Med. Chem., 1993, 36, 1529 CrossRef CAS.
  14. P. Schoeter and D. Hoyer, Naunyn-Schmiedebergs Arch. Pharmacol., 1989, 340, 135.
  15. S. J. Peroutka and B. G. McCarthy, Eur. J. Pharmacol., 1989, 163, 133 CrossRef CAS.
  16. E. Hamel, Current Drugs: Serotonin ID Research Alert, 1996, 1, 19 Search PubMed.
  17. G. R. Martin, Serotonin Receptor Involvement in the Pathogenesis and Treatment of Migraine, in Blue Books on Neurology, eds. S. Silberstein and P. J. Goadsby, Butterworth-Heinemann, 1997 Search PubMed.
  18. E. P. McFadden, J. G. Clarke, G. J. Davies, J. C. Kaski, A. W and M. A. Maseri, New Engl. J. Med., 1991, 324, 648 CAS.
  19. P. Golino, F. Piscione, J. T. Willerson, M. Cappelli-Bigazzi, A. Focaccio, B. Villari, C. Indolfi, E. Russolillo, M. Condorelli and M. Chiariello, New Engl. J. Med., 1991, 324, 641 CAS.
  20. A. Maseri, Circulation, 1990, I1-I3 Search PubMed.
  21. D. J. Fitzgerald, L. Roy, F. Catella and G. A. Fitzgerald, New Engl. J. Med., 1986, 315, 983 CAS.
  22. P. B. Bradley, G. Engel, W. Feniuk, J. R. Fozard, P. P. A. Humphrey, D. N. Middlemiss, E. J. Mylecharane, B. P. Richardson and P. R. Saxena, Neuropharmacology, 1986, 25, 563 CrossRef CAS.
  23. A. L. Scherbel and J. N. Harrison, Angiology, 1959, 10, 29 Search PubMed.
  24. G. P. Moloney, A. D. Robertson, G. R. Martin, S. MacLennan, N. Mathews, S. Dodsworth, Pang Yih Sang, C. Knight and R. C. Glen, J. Med. Chem., 1997, 40, 2347 CrossRef CAS.
  25. J. Saunders, M. Cassidy, S. B. Freedman, E. A. Harley, I. L. Iverson, C. Kneen, A. MacLeod, K. J. Merchant, R. J. Snow and R. Baker, J. Med. Chem., 1990, 33, 1128 CrossRef CAS.
  26. C. J. Swain, R. Baker, C. Kneen, J. Moseley, J. Saunders, E. M. Seward, G. Stevenson, M. Beer, J. Stanton and K. Watling, J. Med. Chem., 1991, 34, 140 CrossRef CAS.
  27. L. J. Street, R. Baker, J. L. Castro, M. S. Chambers, A. R. Guiblin, S. C. Hobbs, V. G. Matassa, A. J. Reeve, M. S. Beer, D. N. Middlemiss, A. J. Noble, J. A. Stanton, K. Scholey and R. J. Hargreaves, J. Med. Chem., 1993, 36, 1529 CrossRef CAS.
  28. B. S. Orlek, F. E. Blaney, F. Brown, M. S. Clark, M. S. Hadley, J. Hatcher, G. J. Riley, H. E. Rosenberg, H. J. Wadsworth and P. Wyman, J. Med. Chem., 1991, 34, 2726 CrossRef CAS.
  29. G. P. Moloney, G. R. Martin, N. Mathews, A. Milne, H. Hobbs, S. Dodsworth, Pang Yih Sang, C. Knight, M. Williams, M. Maxwell and R. C. Glen, J. Med. Chem., 1998, submitted Search PubMed.
  30. G. P. Moloney, G. R. Martin, N. Mathews, H. Hobbs, S. Dodsworth, Pang Yih Sang, C. Knight, M. Williams, M. Maxwell and R. C. Glen, J. Chem. Soc., Perkin Trans. 1, 1999, 2699 RSC.
  31. (a) E. Nordmann, Chem. Ber., 1884, 17, 2746 Search PubMed; (b) R. Lenaers, C. Moussebois and F. Eloy, Helv. Chim. Acta, 1962, 45, 441 CAS.
  32. B. E. Cantrell, Eli Lilly and Company, European Patent EP 0 506 478 A1, 1992.
  33. R. C. Glen, G. R. Martin, A. P. Hill, R. M. Hyde, P. M. Woolard, J. A. Salmon, J. Buckingham and A. D. Robertson, J. Med. Chem., 1995, 38, 3566 CrossRef CAS; P. Woolard and J. A. Salmon, unpublished results.
  34. G. P. Moloney, G. R. Martin, N. Mathews, H. Hobbs, S. Dodsworth, Pang Yih Sang, C. Knight, M. Maxwell and R. C. Glen, under preparation.
  35. G. R. Martin and S. J. MacLennan, Naunyn-Schmiedebergs Arch. Pharmacol., 1990, 342, 111 CAS.
  36. S. J. MacLennan and G. R. Martin, Br. J. Pharm., 1992, 107, 418 CAS.
  37. P. Leff and G. R. Martin, ‘Differences in agonist dissociation constant estimates for 5-HT and 5-HT2 receptors: a problem of acute desensitization?’, Br. J. Pharmacol., 1998, 95, 569 Search PubMed.
  38. P. Woolard and J. A. Salmon, unpublished results.
  39. Sybyl 6.1 molecular modelling package, Tripos Associates, St Louis MO 63144, U.S.A., 1992.
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