NMDA RECEPTOR ANTAGONISTS THAT SPARE LTP

谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型已被发现， 涉及多种神经病理学，包括缺血性 脑损伤（中风），头部创伤，脊髓损伤，癫痫， 神经退行性疾病如阿尔茨海默病和痛觉过敏 states.然而，NMDA拮抗剂作为治疗剂的发展， 受到有害副作用的阻碍，例如 认知障碍。我们实验室的研究发现了一种新的 一类称为芳基烷基胺的NMDA拮抗剂， 并通过一种新的机制。我们初步发现 实验表明，芳基烷基胺不能抑制诱导 强直刺激诱导的Schaffer核长时程增强 侧支-CA 1锥体细胞突触，因此，是第一类 不阻断LTP诱导的有效和选择性NMDA拮抗剂 in this pathway途径.由于LTP可能代表某些形式的细胞基础， 这一发现表明，药物是从 芳基烷基胺可能对认知缺乏作用。拟议的研究将 通过以下方式扩展这一初步结论：（1）审查其他， 结构不同的芳烷基胺，（2）和通过利用 额外的、更生理的电刺激模式， 引发LTP这些研究将有助于我们评估芳烷基胺作为 用于开发新一类治疗剂的先导结构， 神经系统疾病的特点是他们的倾向下降， 损害认知。

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in a variety of neurological pathologies including ischemic brain damage (stroke), head trauma, spinal cord injury, epilepsy, neurodegenerative disorders such as Alzheimer's Disease, and hyperalgesic states. The development of NMDA antagonists as therapeutants, however, has been hampered by the occurrence of deleterious side effects such as the impairment of cognition. Studies in our laboratory have identified a new class of NMDA antagonists termed arylalkylamines which act at a unique site and by a novel mechanism. We have discovered in preliminary experiments that arylalkylamines fail to inhibit the induction of tetanization-induced long-term potentiation (LTP) at the Schaffer collateral-CAl pyramidal cell synapse and, therefore, are the first class of potent and selective NMDA antagonists which do not block LTP induction in this pathway. As LTP may represent the cellular basis for certain forms of learning and memory, this finding suggests that drugs developed from arylalkylamines may lack effects on cognition. The proposed studies will expand on this preliminary finding by (1) the examination of other, structurally dissimilar, arylalkylamines, (2) and by the utilization of additional, more physiological, patterns of electrical stimulation to elicit LTP. Such studies will aid in our evaluation of arylalkylamines as lead structures for the development of a new class of therapeutants for neurological disorders distinguished by their decreased propensity to impair cognition.