Identification of Specific Modulators of NR3-containing Glutamate Receptors

描述（由申请人提供）：谷氨酸受体（NMDAR）的n -甲基- d -天冬氨酸亚型对正常中枢神经系统（CNS）功能至关重要。然而，NMDARs的过度激活，特别是与突触受体相反的突触外受体，至少在一定程度上介导了许多神经系统疾病中的神经元或突触损伤。NMDAR在正常和异常中枢神经系统功能中的双重作用对旨在改善或减轻发育障碍和神经系统疾病的可能治疗策略施加了重要限制：必须在不干扰其正常功能的情况下阻断过度的NMDAR活性。我们提出的一种方法是利用抑制效应

DESCRIPTION (provided by applicant): The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) is essential for normal central nervous system (CNS) function. However, excessive activation of NMDARs, particularly of extrasynaptic as opposed to synaptic receptors, mediates, at least in part, neuronal or synaptic damage in many neurological disorders. The dual role of NMDARs in normal and abnormal CNS function imposes important constraints on possible therapeutic strategies aimed at ameliorating or abating developmental disorders and neurological disease: blockade of excessive NMDAR activity must be achieved without interference with its normal function. One approach we propose is to utilize the inhibitory effect of a novel family of NMDAR subunits, the NR3A and NR3B, to downregulate excessive activity of NMDARs by affecting channel permeability. NR3 subunits have a unique structure in the channel region, which contributes to decreased magnesium sensitivity and calcium permeability. Additionally, glycine binding to the ligand-binding domain (LBD) of NR3 is essential for NR1/NR3 receptor activation, suggesting a critical role of the NR3 LBD in activation of NR3-containing heteromeric receptors. Also, compared to NR1, the NR3 LBD manifests differential sensitivity to NR1 agonists and antagonists, suggesting a unique structure of the NR3 LBD. However, currently there is no NR3-selective agonist, antagonist, or modulator. Therefore, we will utilize structural/functional properties of the NR3 LBD to design screening assays to discover chemical probes that selectively modulate NR3-containing receptors. NR3-containing NMDARs in neurons and myelin may be involved in more neurological diseases than previously thought, especially in so called "white matter" diseases, including multiple sclerosis, cerebral palsy (periventricular leukomalacia), and spinal cord injury. These new NR3 chemical probes identified in our screening efforts will not only be useful for further characterization of NR3-containing receptors in vitro and in vivo, but also may prove useful as drugs for neuroprotection. Accordingly, the Specific Aims of this proposal are as follows: Specific Aim 1. Implement an HTS assay for the NR3-LBD and screen a large-scale compound collection for identification of NR3 modulators. Specific Aim 2. Perform secondary assays for identification of hits that selectively bind to NR3 subunits and modulate NR3-containing receptors. Specific Aim 3. Establish and utilize structure-activity relationship (SAR) for optimization of the hits that modulate NR3-containing receptors.