Bioorganic & medicinal chemistry
May 1, 2012
Kimberly M Lovell, Tamara Vasiljevik, Juan J Araya et al.
35 citations
A palladium-catalyzed cross-coupling reaction (Liebeskind-Srogl) applied to a modified natural product scaffold produces ketone analogs of salvinorin A at neutral pH and room temperature, expanding synthetic access to this class. A one-step microwave method converts salvinorin A to its 12-epimer, previously requiring multiple steps. Several new analogs (alkene 9 and aromatic compounds 12, 19, 23, 25, 26) retain affinity and selectivity for kappa opioid receptors (KOP), and the furan-2-yl analog (31) shows similar affinity to the parent compound. These results indicate that diverse aromatic groups attached to the decalin core may be tolerated by KOP receptors, potentially yielding additional ligands.
The Journal of pharmacology and experimental therapeutics
June 1, 2012
Eduardo R Butelman, Michael Caspers, Kimberly M Lovell et al.
27 citations
The major efflux transporter P-glycoprotein at the blood-brain barrier modulates the central nervous system effects of the hallucinogen salvinorin A. Pretreatment with either the competing substrate loperamide (0.032-0.32 mg/kg) or the selective blocker tariquidar (0.32-3.2 mg/kg) dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation, in nonhuman primates. Neither agent affected the effects of U69,593, a κ-agonist that is a poor P-glycoprotein substrate. Tariquidar (3.2 mg/kg) also increased peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These findings demonstrate that P-glycoprotein activity can influence salvinorin A's behavioral effects and CNS entry.
Analytical methods : advancing methods and applications
December 21, 2013
Michael J Caspers, Todd D Williams, Kimberly M Lovell et al.
6 citations
A method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) measures the hallucinogen salvinorin A in non-human primate cerebrospinal fluid (CSF) and human plasma. For CSF, simple dilution with acetonitrile and formic acid replaces solid phase extraction. Human plasma requires centrifugation, then loading onto a C18 SPE column. A shallow acetonitrile/water gradient elutes the compound. Limits of quantification are 0.0125 ng/mL for CSF and 0.05 ng/mL for plasma. Interday precision and accuracy are below 1.7% and 9.42% for CSF and 3.47% and 12.37% for plasma. The method determined salvinorin A concentrations in a Rhesus monkey study and a human trial using behaviorally active doses.