The synthesis and in vitro evaluation of a new series of salvinorin A analogues substituted at the C(2) position with natural amino acids is reported. Compound 12, containing Val, displayed high affinity and full agonist activity at the kappa-opioid receptor. Analogues with bulky and/or aromatic residues were inactive, showing the importance of size and electronegativity of C(2)-substituents...
Salvinorin A, the most potent naturally occurring hallucinogen, has attracted an increasing amount of attention since the kappa-opioid receptor (KOR) was identified as its principal molecular target by us [Roth, B. L., et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 11934-11939]. Here we report the design, synthesis, and biochemical characterization of novel, irreversible, salvinorin A-derived...
Novel semisynthetic analogs of salvinorin A, a full agonist having extraordinary affinity as well as selectivity for the κ-opioid receptor (KOR), were obtained in good yields. The derivatives are remarkable for their unusual and unique hemiacetal structure in the salvinorin series of compounds. The formation of the hemiacetal occurs with epimerization at C-12, thus preserving the original...
To study drug-receptor interactions, new thio-derivatives of salvinorin A, an extremely potent natural kappa-opioid receptor (KOR) agonist, were synthesized. Obtained compounds were examined for receptor binding affinity. Analogs with the same configuration at carbon atom C-2 as in natural salvinorin A showed higher affinity to KOR than their corresponding epimers.
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Salvinorin A ((2S,4aR,6aR,7R,9S,10aS, 10bR)-2H-naphtho[2,1-c]pyran-7-carboxylic acid, 9-(acetyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo methyl ester, 1, CAS 83729-01-5) has been shown to bind with high affinity and selectivity to the kappa-opioid receptor (KOR) as an agonist. Bioisosteres of 1 were developed and biologically evaluated in binding and functional assays. The C-2...
Salvinorin A is a naturally occurring hallucinogenic diterpenoid from the plant Salvia divinorumthat selectively and potently activates kappa-opioid receptors (KORs). Salvinorin A is unique in that it is the only known lipid-like molecule that selectively and potently activates a G-protein coupled receptor (GPCR), which has as its endogenous agonist a peptide; salvinorin A is also the only...
Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity but that the lactone and ketone functionalities are not. Other salvinorins showed...
kappa-opioid receptors (KORs) represent the principal site of action of dynorphin and related neuropeptides. Recently, Salvinorin A--a naturally occurring neoclerodane diterpene hallucinogen was identified to be a highly selective KOR agonist. In this brief review we summarize the known chemistry, pharmacology and biology of salvinorin A. Because salvinorin A profoundly alters human...