Synthesis and in vitro evaluation of salvinorin A analogues: Effect of configuration at C(2) and substitution at C(18)

doi:10.1016/j.bmcl.2006.05.093

Bioorganic & Medicinal Chemistry Letters

Volume 16, Issue 17, 1 September 2006, Pages 4679-4685

https://doi.org/10.1016/j.bmcl.2006.05.093 Get rights and content

Abstract

κ-opioid receptor ligands have raised interest for their apparent effects on mood. The potent and selective κ-agonist salvinorin A has short-lasting (15 min) depressive-like effects in rats in behavioral models used to study mood disorders. Two series of salvinorin derivatives modified at C(2) and C(18), respectively, were synthesized and their κ-opioid receptor affinities, potencies, and efficacies were evaluated using in vitro receptor binding and biochemical functional assays. Modification at C(2) yielded potent κ-agonists that are predicted to have improved metabolic stability (14a, 15a) or increased water solubility (10b). Our preliminary SAR study at C(18) suggested that this part of the molecule interacts with a tight lipophilic pocket of the κ-receptor.

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Acknowledgments

We thank Dr. Zhongze Ma and Dr. David Lee for providing salvinorin A, and Dr. Thomas Munro for his review and comments on the manuscript. This work was supported by the Stanley Medical Research Institute and NIH Grants DA04745 and DA 17302 (to L-.Y.L-.C.).

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Synthesis and in vitro evaluation of salvinorin A analogues: Effect of configuration at C(2) and substitution at C(18)

Abstract

Graphical abstract

Section snippets

Acknowledgments

J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Tetrahedron

Tetrahedron Lett.

Bioorg. Med. Chem. Lett.

J. Pharmacol. Exp. Ther.

Science

J. Pharmacol. Exp. Ther.