The synthesis, conformation and antimuscarinic properties of ketone analogues of tropane esters

Abstract

A synthesis of the ketone analogues of three naturally occurring tropane esters has been developed and one of the ketones has been evaluated for its efficacy as a muscarinic acetylcholine receptor (mAChR) antagonist in guinea-pig ileum. The ketone analogue of apoatropine displayed an IC₅₀ value in the micromolar range when compared to atropine, which has antagonist activity in the nanomolar range. The conformational change in replacing the bridging oxygen of the ester moiety by CH₂ has been assessed by X-ray structure analysis of one of the compounds and has been evaluated more widely in a Cambridge Crystallographic Database survey. The structural data reveals that both the tropane esters and tropane ketones adopt similar conformations.

References

1. M. Lounasmaa, The Alkaloids, Academic Press: New York, 1988, 33, ch. 1.
2. M. Lounasmaa and T. Tamminen, The Alkaloids, Academic Press: New York, 1993, 44, ch. 1.
3. J. H. Brown, Atropine, Scopolomine and Related Antimuscarinic Drugs, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eds. J. G. Hardman and L. E. Limbird, 8^th edn., 1990, ch. 8, pp. 150–165, Pergamon Press.
4. G. H. Cocolas, in Cholinergic Drugs and Related Agents, in Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, eds. J. N. Delgado and W. A. Remers, 9^th edn., J. B. Lippincott Company: New York, 1991, ch. 12, pp. 471–477.
5. H. Gozan and M. Langois, Central and peripheral 5'HT₃ receptors, Academic Press, London, 1992, pp. 59–88.
6. M. Langlois, J. L. Soulier, D. Yang, B. Bremont, C. Florac, V. Rampillon and A. Giudice, Eur. J. Med. Chem., 1993, 28, 869.
7. Z. G. Gao, W. Y. Cui, L. Wang and C. G. Liu, Arch. Int. Pharmacodyn. Ther., 1996, 331, 124.
8. T. Schmeller, F. Sporer, M. Sauerwein and M. Wink, Pharmazia, 1995, 50, 493.
9. Z. G. Gao, W. Y. Cui, B. Y. Liu, C. G. Liu and L. Wang, J. Pharm. Pharmacol., 1997, 49, 315.
10. D. W. Robertson, W. B. Lacefield, W. Bloomquist, W. Pfeifer, R. L. Simon and M. L. Cohen, J. Med. Chem., 1992, 35, 310.
11. W. C. Evans and P. G. Treagust, Phytochemistry, 1973, 12, 2077.
12. W. C. Evans and K. P. A. Ramsey, Phytochemistry, 1983, 22, 2219.
13. S. Siddiqui, N. Sultana, S. S. Ahmed and S. I. Haider, J. Nat. Prod., 1986, 49, 511.
14. B. J. Calvert and J. D. Hobson, J. Chem. Soc., 1965, 2723; M. Kato, K. Ito, S. Nishino, H. Yamakuni and H. Takasugi, Chem. Pharm. Bull., 1995, 43(8), 1351.
15. C. L. Zirkle, E. L. Anderson, P. N. Craig, F. R. Gerns, Z. K. Indik and A. M. Pavlo, J. Med. Pharm. Chem., 1962, 5, 341.
16. T. Baasov and M. Sheves, J. Am. Chem. Soc., 1985, 107, 7524.
17. S. Czernecki, C. Georgoulis, C. L. Stevens and K. Vijayakumaran, Tetrahedron Lett., 1985, 26, 1699.
18. Y.-S. Cheng, W.-L. Liu and S.-H. Chen, Synthesis, 1980, 223.
19. A. J. Mancuso, S.-L. Huang and D. Swern, J. Org. Chem., 1978, 43, 2480.
20. R. J. Gritter and T. J. Wallace, J. Org. Chem., 1959, 24, 1051.
21. F. H. Allen and O. Kennard, Chem. Des. Autom. News, 1993, 8, 1 and 31.
22. A. McL. Mathieson, Tetrahedron Lett., 1965, 4137.
23. W. B. Schweizer and J. D. Dunitz, Helv. Chim. Acta, 1982, 65, 1547.
24. Department of Pharmacology, University of Edinburgh, Pharmacological Experiments on Isolated Preparations (2nd edn.), Longman Group Ltd., 1971, p. 58.
25. M. Elorriaga, E. Anselmi, J. M. Hernandez, P. D'ocon and D. Ivorra, J. Pharm. Pharmacol., 1996, 48, 817.
26. F. I. Carroll, P. Abraham, K. Parham, R. C. Griffith, A. Ahmad, M. M. Richard, F. N. Padilla, J. M. Witkin and P. K. Chiang, J. Med. Chem., 1987, 30, 805.
27. J. M. Karle, I. L. Karle, R. K. Gordon and P. K. Chiang, Acta Crystallogr., Sect. B, 1992, 48, 208.
28. G. M. Sheldrick, SHELXTL, ver. 5.10, Bruker Analytical X-ray Systems, Madison, WI, USA, 1997.
29. H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 876.