Journal of natural products
April 25, 2011
Anthony Lozama, Christopher W Cunningham, Michael J Caspers et al.
40 citations
New chemical methods using microwave heating enabled the first successful Diels-Alder cycloaddition reactions on the furan ring of salvinorin A, a neoclerodane diterpene natural product. This approach introduced electron-withdrawing groups and bulky aromatic rings at the C-12 position. Some of the resulting cycloadducts, specifically dimethyl- and diethylcarboxylate analogues, retained affinity and selectivity for kappa opioid receptors and acted as full agonists. However, converting these cycloadducts into planar phenyl ring systems reduced their receptor affinity. The work provides a novel strategy for rapidly exploring structure-activity relationships of furan-containing natural products.
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.
Topics in current chemistry
January 1, 2011
Kimberly M Lovell, Katherine M Prevatt-Smith, Anthony Lozama et al.
17 citations
Salvinorin A, a unique compound, stands out as the first opioid ligand discovered without a basic nitrogen, challenging traditional understanding. Researchers developed sophisticated synthetic methods to recreate and modify its complex structure, which features seven chiral centers. By focusing on specific structural changes, they successfully created new analogs. These efforts yielded promising compounds with diverse and interesting biological activities, highlighting the power of chemical synthesis in drug discovery.
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.
Organic & biomolecular chemistry
September 21, 2009
Denise S Simpson, Kimberly M Lovell, Anthony Lozama et al.
Modifying the furan ring of salvinorin A, the active component of Salvia divinorum, produced new compounds with activity at opioid receptors. A computational study predicted salvinorin A to be a reproductive toxicant in mammals, suggesting its use may have adverse effects. Two new compounds, piperidine 21 and thiomorpholine 23, were identified as selective partial agonists at kappa opioid receptors. This suggests further structural changes could yield ligands with good opioid receptor selectivity but lower toxicity.