Cage compounds as blockers of GABA and glycine receptor-channels

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GABA and glycine are the major inhibitory neurotransmitters in the brain and, together with their associated receptors (GABARs and GlyRs), they are responsible for rapid inhibitory neurotransmission. The importance of these receptors in brain function and dysfunction is emphasized by their implication in a number of hereditary and more complex disorders, such as anxiety, epilepsy, dementias, alcoholism and lack of motor control. Many compounds act on these receptor-channels and modulate their function and some of these are used clinically (e.g., anti-anxiolytics, some anaesthetics). Recently, some compounds which inhibit these receptor-channels (typically convulsant drugs) have, in low doses, been shown to enhance learning and memory and to provide some improvement in different senile dementias. Ginkgo biloba extract is used worldwide and has been shown to be effective in the symptomatic treatment of cognitive disorders associated with old age dementia and Alzheimer's disease. Some of the active constituents, the ginkgo compounds, inhibit the GABA and glycine receptors but, importantly for therapeutic activity, are not convulsants. It is suspected that these and related compounds bind within the pore of these receptor-channels to mediate their inhibition, although the data is conflicting and no-one precisely knows how they act. This project aims to directly investigate how the ginkgo compounds, and the related compound picrotoxinin, act on the GABA and glycine receptors, and to determine the site on the protein to which they bind. Furthermore, this project will shed some light on why picrotoxin is a convulsant but the gingko compounds are not. A more thorough understanding of exactly how these compounds work will give us important information on how these receptor-channels work and will lead to the development of better therapeutics, particularly those targeted against old-age dementias and Alzheimers disease.