MEDICINAL CHEMISTRY
Allopregnanolone is an anaesthetic steroid and its 11-keto derivative, alphaxalone, has been used clinically as an iv general anaesthetic agent. Recently there have been two significant discoveries associated with structure-activity relationships of this class of modulator of the GABAA receptor. The allene derivative (structure below) has potent binding activity; and the phenyl analogue, 17PA, has been shown to be an antagonist at the relevant binding site on GABA A receptors. This project will investigate structure-activity studies of analogues of allopregnanolone with different substituents at 17 position.
Allopregnanolone Allene derivative 17PA '
The measurement of mycotoxins and pesticides levels by the ELISA (Enzyme-Linked ImmunoSorbent Assay) technique offers advantages of simplicity, specificity and sensitivity. A key step in the development of such an immunoassay is the synthesis of a hapten -a derivative to link the molecule to a carrier protein (to raise antibodies) or to an enzyme (to quantify the mycotoxin or pesticide by a colour reaction). This project to synthesise new haptens is part of a continuing collaboration with Professor Ivan Kennedy in the Faculty of Agriculture, Food and Natural Resources. Students undertaking this project would investigate new methods to introduce linker arms for attaching molecules carrier proteins or to enzymes. Particular reactions to be studied include the use of 4-bromobutenoic acid to introduce a 4-carbon linker arm onto the parent compound.
GRAHAM JOHNSTON, RUJEE DUKE, TINA HINTON
NEUROPHARMACOLOGY
The physiological basis of action of many herbal remedies is still relatively unknown, even though these compounds are commonly consumed. GABA-A receptors play an important role in most brain functions, and have been shown to be important targets of plant extracts, such as resveratrol from red wine, flavanones from chamomile tea, and thujone from absinthe, as well as herbs such as kava kava, gingko, valerian and passion flower. Projects will involve investigating the effects of extracts and active constituents from commonly consumed herbal remedies mentioned above on GABA-A receptor function.
Projects will involve the isolation and characterization of active constituents of herbal remedies using techniques such as:
Bilobalide, and ginkgolides A, B, and C are the active constituents of the 50:1 ginkgo Ginkgo biloba leaf extract used worldwide for the symptomatic treatment of cerebral and peripheral insufficiency and dementia. These compounds may be involved in the cognition enhancing effect of the ginkgo extract. We have shown that they were noncompetitive blockers of GABA receptors with a similar mechanism of action to that of the chloride channel blocker picrotoxinin. GABA-A and GABA-C receptors are members of a super-family of ligand-gated ion channel receptors that also include the nicotinic acetylcholine (nACh) and serotonin 5-HT3 receptors. The amino acids in the subunit transmembrane proteins that make up the channel of these receptors are highly conserved in this super-family. Picrotoxinin blocks the channel of all members in this superfamily with wide variation in potencies. It is most potent at GABA receptors and only weakly to moderately potent at glycine, nACh and 5-HT3 receptors. Bilobalide, ginkgolide A, B and C are structurally similar to picrotoxinin. Honours project will involve evaluating the effects of bilobalide, ginkgolide A, B and C on wild type nACh receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methodology.
Projects will involve the biological and pharmacological evaluation of the active constituents of herbal remedies, using techniques such as:
Projects will involve pharmacological evaluation of the active constituents of herbal remedies using techniques such as:
Aspects of these projects may be carried out in collaboration with Mary Collins and Jane Hanrahan in the Faculty of Pharmacy.
Our group uses a multidisciplined approach to research and many different techniques may be learned. We use:
NEUROCHEMISTRY/NEUROPHARMACOLOGY
The possible roles of GABA in schizophrenia are being examined in collaboration with the Schizophrenia Research Institute using facilities provided by the NISAD Centre for Collaborative Human Brain Research at the University of Sydney. Prospective honours students are encouraged to discuss possible projects with the above named researchers.
Date of last update: 4 July 2007
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