Cage compounds as blockers of GABA and glycine receptor-channels

GABA和甘氨酸是大脑中主要的抑制性神经递质，它们与它们的相关受体(GABA和GlyRs)一起负责快速的抑制性神经传递。这些受体在一些遗传性和更复杂的疾病中的作用，如焦虑、癫痫、痴呆、酗酒和缺乏运动控制，强调了这些受体在大脑功能和功能障碍中的重要性。许多化合物作用于这些受体通道并调节它们的功能，其中一些用于临床(如抗焦虑药物、一些麻醉剂)。最近，一些抑制这些受体通道的化合物(典型的惊厥药物)在低剂量下被证明可以增强学习和记忆，并对不同的老年痴呆症提供一些改善。银杏叶提取物在世界各地使用，已被证明对老年痴呆症和阿尔茨海默病相关的认知障碍有有效的治疗作用。一些活性成分，银杏化合物，抑制GABA和甘氨酸受体，但重要的是治疗活性，不是惊厥药。人们怀疑，这些化合物和相关化合物结合在这些受体通道的孔内，以调节它们的抑制，尽管数据相互矛盾，没有人确切地知道它们是如何起作用的。该项目旨在直接研究银杏化合物和相关化合物印防己毒素是如何作用于GABA和甘氨酸受体的，并确定它们与蛋白质结合的位置。此外，这个项目将阐明为什么印防己毒素是一种惊厥剂，而银杏化合物不是。更彻底地了解这些化合物是如何发挥作用的，将为我们提供关于这些受体通道如何工作的重要信息，并将导致更好的疗法的发展，特别是那些针对老年痴呆和阿尔茨海默病的疗法。

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.