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. 2013 May 15;23(10):2860-2.
doi: 10.1016/j.bmcl.2013.03.111. Epub 2013 Apr 4.

Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands

Prabhakar R Polepally  1 , Kate White, Eyal Vardy, Bryan L Roth, Daneel Ferreira, Jordan K Zjawiony
Affiliations

Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands

Prabhakar R Polepally et al. Bioorg Med Chem Lett. .

Abstract

Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective κ-opioid receptor agonist. To better understand the ligand-receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ-, δ- and μ-opioid receptors. Most of the analogues show high affinity to the κ-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki=2nM), analogues 5, 7, and 14 exhibit significant affinity for the κ-receptor (Ki=21, 36 and 39nM).

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Figures

Figure 1
Figure 1
The structures of salvinorin A, 22-thiocyanatosalvinorin A, and salvinorin B.
Scheme 1
Scheme 1
Synthesis of dicarboxylic ester-type salvinorin A analogues 4-12 Reagents and conditions: (a) appropriate acid chloride, Et3N, dry DCM, N2 r.t, 2-3 h, or appropriate acid anhydride, DBU, dry DCM, N2, r.t, 6-8 h.
Scheme 2
Scheme 2
Synthetic route for the designed ligands 13-16. Reagents and conditions: (a) appropriate acid chloride, Et3N, dry DCM, N2, r.t, 3 h, or appropriate acid anhydride, DBU, dry DCM, N2, r.t, 6-8 h.
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