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Investigations Of Salvinorin A: Synthetic Isolation, Quantification, And In Vivo Characteristics
Caspers, Michael J.
Caspers, Michael J.
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Abstract
While many ligands are known to interact with the opioid receptor system, most can be traced back to the common morphine scaffold. In several cases ligands have been developed that are selective for either the mu, kappa, or delta opioid receptors. Selective kappa opioid receptor agonists and antagonists have shown potential to be used to decrease cocaine self-administration and be utilized in the treatment of relapse. The emergence of salvinorin A as a novel scaffold, that selectively interacts with the kappa opioid receptor, retains therapeutic potential with a reduced side effect profile to the current treatments. Traditional mu opioid ligands, such as morphine, have life threatening side effects such as respiratory depression and constipation among other drawbacks like tolerance and dependence. To fully investigate the potential of salvinorin A as a viable alternative for therapeutic treatment it must be isolated in high purity for pharmacological evaluation. In efforts to isolate high purity salvinorin A, a reactive handle was generated that was shown to undergo cycloaddition to the furan ring of salvinorin A. This handle was developed using the reactivity limitations that were also investigated for the Diels-Alder cycloaddition of electron deficient alkenes and alkynes with the salvinorin A furan ring. In order to understand the unique mode of interaction salvinorin A imparts on the opioid receptor system, investigations into the pharmacological profile of salvinorin A were explored. Analytical methods were developed for the identification and quantification of salvinorin A from non-human primate cerebrospinal fluid and human plasma. This method was then exploited to develop a time-course graph for the measurement of in vivo concentrations of salvinorin A in various biological fluids which could be correlated to subjective and biological observations.
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Date
2013-05-31
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Publisher
University of Kansas
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Keywords
Chemistry, LC-MS/MS, Natural Product, Opioid, Opioid Receptor, Salvinorin A, Solid Support Reagent