Associate Professor Jane Hanrahan

Research interests

Design and synthesis of conformationally restricted GABA analogues

GABA (1) is the major inhibitory neurotransmitter in the CNS. It is responsible for maintaining the balance between excitation and inhibition in the brain. Dysfunction of GABA receptors has been implicated in many disease states including schizophrenia, epilepsy and memory loss.

GABA is an extremely flexible molecule, which allows it to act at 3 subtypes of receptors (GABAA, GABAB, and GABAC). By designing analogues of GABA which are structurally restricted in different ways (Figure 1), we are able to target individual receptor subtypes. The compounds are tested on GABA receptors expressed in Xenopus laevis oocytes in collaboration with Dr Mary Collins. Current studies are investigating the design and synthesis of conformationally restrained alkyl phosphinic acids eg (2) as analogues of GABA that are selective GABAC antagonists.

Flavonoids as modulators of GABA receptors (in collaboration with Professor Graham Johnston, Department of Pharmacology)

Flavonoids are found in many foods and drinks eg naringenin in grapefruit, resveratrol in red wine and apigenin in chamomile tea. They are also found in a number of herbal medicines eg, flavonoid glycosides in ginkgo biloba, amentoflavone in St John's Wort. Flavonoids are known to have a wide range of biological activities. We have recently and shown that some flavonoids, both synthetic eg (3) and natural, modulate the action of GABA at the GABAA receptor, possibly via the low affinity benzodiazepine binding site. This action appears to be devoid of many of the side-effects common to benzodiazepines. We have recently developed a rapid semi-synthetic method for the preparation of amentoflavone (4), a biflavonoid that is found in Ginkgo biloba and St John's Wort.

In collaboration with Associate Professor David Hibbs, Faculty of Pharmacy, we are also investigating the charge density of flavonoids using high resolution X-ray crystallography. This information will then be used in the designing of novel compounds with enhanced activity.

GABA release in the Thalamus

The thalamus is the brain's main sensory filter playing a major role in the regulation of consciousness, alertness, arousal, and possibly attention. It is the area where information is received and relayed to other areas of the brain, making it of particular interest in disorders such as epilepsy, memory dysfunction and schizophrenia because of the part it plays in processing information. The thalamus has been shown to be dysfunctional in the earliest stages of schizophrenia

We have recently found that the GABAC antagonist, TPMPA, increases K+-stimulated GABA release in the thalamic slices (250 microm x 1000 microm) but not in smaller thalamic slices (250 microm x 250 microm). This suggests that integrity of the neuronal circuitry is required. We are currently investigating the mechanism of this GABA mediated GABA release in the thalamus. We are currently continuing investigations in this area to determine more about the neuronal circuitry involved in these pathways.

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