SYNTHETIC NEUROPROTECTIVE GLUTAMATE RELEASE BLOCKERS

缺血时神经元的损伤是由谷氨酸的过度释放引起的 从大脑神经末梢。 我们发现，使用新的快速动力学 在P.l.中开发的方法。的实验室，某些替代品 胍类和相关化合物是钙依赖性 从脑神经末梢释放谷氨酸和多巴胺。 其中一 表现出选择性阻断谷氨酸释放。 这些化合物，我们 假设作为突触前钙通道拮抗剂，可能 用作药物，以限制中风和创伤性脑缺血损伤 脑损伤患者 我们的目标是识别和合成额外的 具有改进的效力和特异性的取代的胍衍生物， 阻断神经递质的释放。 为此，我们将采用 分子模拟工具和定量构效关系 分析. 它们的作用机制和拮抗的选择性 突触前钙通道将由电生理学定义， 放射性同位素通量和放射性配体结合技术。 他们将 在中风动物模型中测试神经保护功效， 剑桥神经科学和研究人员合作， 马萨诸塞州总医院和康奈尔医疗中心。 我们的初步 体内研究已经证明了通过取代的胍 阻止神经递质的释放

Neuronal damage in ischemia is initiated by excessive release of glutamate from brain nerve terminals. We have discovered, using novel rapid kinetic methodology developed in the P.l.'s laboratory, that certain substituted guanidines and related compounds are antagonists of calcium-dependent release of glutamate and dopamine from brain nerve terminals. One of these exhibits selective block of glutamate release. Such compounds, which we hypothesize to act as antagonists of presynaptic calcium-channels, may be employed as drugs to limit ischemic brain damage in stroke and traumatic brain injury patients. Our goal is to identify and synthesize additional substituted guanidine derivatives of improved potency and specificity for blockade of neurotransmitter release. To that end, we will employ molecular modeling tools and quantitative structure activity relationship analysis. Their mechanism of action and selectivity for antagonism of presynaptic calcium channels will be defined by electrophysiological, radioisotopic flux, and radioligand binding techniques. They will be tested for neuroprotective efficacy in animal models of stroke, both at Cambridge NeuroScience and in collaboration with investigators at the Massachusetts General Hospital and Cornell Medical Center. Our preliminary in vivo studies have demonstrated neuroprotection by substituted guanidines which block neurotransmitter release.