Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2)

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Abstract

Salvinorin A is the only known non-nitrogenous and specific κ-opioid agonist. A series of salvinorin A derivatives were prepared and tested for in vitro activity at the κ-opioid receptor. Unsubstituted carbamate 9 was a potent κ-agonist (EC50 = 6.2 nM) and should be more stable than salvinorin A toward metabolic transformations. Compound 10, containing an N-methyl carbamate at C(2), showed partial agonist activity with 81% efficacy when compared with the full agonist U50,488H. No antagonist ligands were observed.

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Acknowledgements

This work was supported by the Stanley Medical Research Institute and by NIH Grants DA 04745, DA 17302, and P30 DA 13429.

References and notes (20)

  • K. Tidgewell et al.

    Bioorg. Med. Chem. Lett.

    (2004)
  • P. Kocovsky

    Tetrahedron Lett.

    (1986)
  • A. Pfeiffer et al.

    Science

    (1986)
  • S.L. Walsh et al.

    Psychopharmacology

    (2001)
  • S.D. Mague et al.

    J. Pharmacol. Exp. Ther.

    (2003)
  • M.S. Todtenkopf et al.

    Psychopharmacology

    (2004)
  • M. Eguchi

    Med. Res. Rev.

    (2004)
  • B.L. Roth et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • M. Mowry et al.

    Psychoact. Drugs

    (2003)
There are more references available in the full text version of this article.

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