Dissertation/Thesis Abstract

The Chemistry of Salvia divinorum
by Munro, Thomas Anthony, Ph.D., University of Melbourne (Australia), 2006, 283; 3304556
Abstract (Summary)

Salvia divinorum is a hallucinogenic sage used to treat illness by the Mazatec Indians of Mexico. Salvinorin A (1a), a neoclerodane diterpenoid isolated from the plant, is a potent, selective agonist at the κ opioid receptor (KOR), and is the first non-nitrogenous opioid. The plant is used recreationally as a hallucinogen, but is unpopular due to its dysphoric effects. 1a has been prohibited in Australia under an invalid systematic name.

An early report of psychoactive alkaloids in S. divinorum proved to be irreproducible. Similarly, tests in mice suggesting the presence of psychoactive compounds other than 1a were confounded and therefore unreliable.

In this work, an improved isolation method for 1a was developed, using filtration through activated carbon to decolourise the crude extract. Six new diterpenoids were isolated: salvinorins D–F (1d–1f ) and divinatorins A–C (28a–28c). Five known terpenoids not previously reported from this species were also isolated.

The structure–activity relationships of 1a were evaluated via selective modifications of each functional group. Useful synthetic methods are reviewed, including the first thorough review of furanolactone hydrogenations. Testing of the derivatives at the KOR suggests that the methyl ester and furan ring of 1a are required for activity, but that the lactone and ketone functionalities are not. Other compounds from S. divinorum did not bind to the KOR, suggesting that 1a is the plant's active principle.

The structure of the 8-epimer of 1a, reported previously without supporting evidence, was firmly established. This epimerisation proved to be a general phenomenon among salvinorins and related furanolactones, occurring via enolisation of the lactone. The more complex mechanism proposed by Koreeda and co-workers was inconsistent with subsequent data. Under strongly basic conditions, autoxidation of 1a occurred to give the enedione 59 as the major product. A previously proposed structure was shown to be incorrect.

Salvinorins and divinatorins were tested and found to be inactive against insects, bacteria, fungi, HIV, tumour cell lines and protein synthesis.

Indexing (document details)
Advisor: Rizzacasa, Mark
Commitee:
School: University of Melbourne (Australia)
School Location: Australia
Source: DAI-B 69/03, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmacology, Organic chemistry
Keywords: Divinatorin, Salvia divinorum, Salvinorin A, kappa-Opioid receptor
Publication Number: 3304556
ISBN: 978-0-549-50622-5
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