EXCITATORY AMINO ACIDS--ROLE IN CNS DISORDERS

该计划项目的长期目标是促进现有知识的发展 兴奋性氨基酸(EAA)在中枢神经系统疾病中的作用 这一知识是开发新的药理制剂的基础 在治疗神经疾病方面很有效。为了实现这一目标， 每个首席调查员将使用一套策略，这些策略 以下是：(1)将寻求关于每个角色的新信息 中枢神经系统疾病中的EAA亚型。到目前为止，每个特定的EAA受体 子类型不能与特定的中枢神经系统功能或 功能障碍。澄清NMDA、QuisQualate和NMDA的关系 红藻氨酸受体将为特定功能和功能障碍提供一种 为新药开发奠定基础。(2)将寻求新的资料 士的宁不敏感甘氨酸受体在变构中的作用 NMDA受体的调节。聚焦于这种特定的变构 调制位点是理解中枢神经系统的起点 以及开发新一代治疗精神障碍的药物 癫痫、肌肉痉挛、学习和记忆障碍 损伤、神经元死亡、脊髓损伤和老年人疾病 心血管和呼吸系统。(3)将寻求新的信息 EAA受体信号转导机制的研究。地产代理监管局的一个特点 受体是它们诱导形成多个 可能与其他传入刺激整合的细胞内信息 以产生不同的神经元反应。中每个步骤的标识 细胞内信息的形成将有助于阐明分子 细胞功能正常和功能紊乱的机制，以及 为开发作用超过一步或几步的药物提供基础 EAA受体。(4)将寻求关于其他组织的作用的新信息 神经递质系统可以调节大脑和大脑中的EAA系统 脊髓。我们的假设是，监管局制度可能被 其他调节EAA传递或作用的神经递质系统 独立地产生中枢神经系统障碍。对这些其他的解释 发射系统将为新药的开发提供基础， 或者是治疗神经疾病的药物组合。总而言之， 中枢神经系统功能障碍与一种特定的EAA的关系 受体，绕过主要识别部位，专注于 NMDA受体复合体的调制位点，通过以下方式绕过EAA受体 专注于第二信使系统，并阐明其他 与EAA递质系统相互作用的神经递质系统提供 设计治疗多种疾病的新药的机会 中枢神经系统紊乱。

The long range goal of the program project is to advance current knowledge of the role of excitatory amino acids (EAA) in CNS disorders, and to use this knowledge as a basis for developing new pharmacological agents effective in the treatment of neurological disorders. To achieve this goal, a set of strategies will be used by each principal investigator and these are as follows: (1) New information will be sought on the role of each subtype of EAA in CNS disorders. As yet, each particular EAA receptor subtype cannot be clearly correlated with specific CNS functions or dysfunctions. Clarification of the relationship of NMDA, quisqualate and kainate receptors to specific functions and dysfunctions will provide one basis for new drug development. (2) New information will be sought on the role of the strychnine-insensitive glycine receptor in allosteric modulation of the NMDA receptor. Focusing on this specific allosteric modulatory site represents a point of departure for understanding CNS disorders and for the development of a new generation of drugs for disorders such as epilepsy, muscle spasticity, learning and memory impairments, neuronal death, spinal cord trauma, and diseases of the cardiovascular and respiratory system. (3) New information will be sought on the mechanism of signal transduction at EAA receptors. A feature of EAA receptors is their ability to induce the formation of multiple intracellular messages which may be integrated with other incoming stimuli to produce distinct neuronal responses. Identification of each step in the formation of intracellular messages will help elucidate molecular mechanisms for normal cell function and disordered cell function, and provide a basis for developing drugs that act one or several steps beyond the EAA receptor. (4) New information will be sought on the role of other neurotransmitter systems that can regulate the EAA systems in the brain and spinal cord. Our assumption is that the EAA system may be manipulated by other neurotransmitter systems that either regulate EAA transmission or act independently to produce CNS disorders. Elucidation of these other transmitter systems will provide a basis for the development of new drugs, or a combination of drugs for treating neurological disorders. In summary, concentration on relating disorders of CNS function to a specific EAA receptor, side stepping the primary recognition site and focusing on the modulator site of the NMDA receptor complex, bypassing the EAA receptor by focusing on second messenger systems, and elucidating other neurotransmitter systems that interact with EAA transmitter systems offer the opportunities for the design of new drugs to treat a wide spectrum of CNS disorders.