Molecular Pharmacology of the System xc- Glutamate/Cystine Antiporter

描述（由申请人提供）：该项目的总体目标是推进xc-谷氨酸/胱氨酸反转运体（Sxc-）系统的新型抑制剂的发现和开发，特别是针对转运体上新发现的变构位点。Sxc-是连接l -胱氨酸（L-Cys2）进口和l -谷氨酸（L-Glu）出口的专性交换物。sgc -功能在中枢神经系统中尤为重要，因为它介导谷胱甘肽（GSH）合成和氧化保护所需的重要含硫氨基酸的摄取，同时产生一种兴奋性神经递质的外排，这种神经递质以其对快速和缓慢突触信号传导、突触可塑性和兴奋性毒性病理的贡献而闻名。新出现的证据还表明，SxC-活性的变化与多种中枢神经系统疾病的潜在病理机制有关，其中最突出的是神经胶质性脑肿瘤和药物成瘾/复发。不幸的是，我们对sgc -在中枢神经系统中的功能重要性的认识日益增长，迅速超过了有效和选择性小分子调节转运蛋白活性的可用性。我们小组最近的合成和基于sar的药理学研究发现了一系列新的有效的非竞争性Sxc抑制剂，我们假设它们与转运体上底物结合位点附近的至少两个不同的亲脂结构域相互作用。我们对

DESCRIPTION (provided by applicant): The overall goal of this project is to advance the discovery and development of novel inhibitors of the system xc- glutamate/cystine antiporter (Sxc-), specifically targeting a newly identified allosteric site on the transporter. Sxc- is an obligate exchanger that links the import of L-cystine (L-Cys2) with the export of L-glutamate (L-Glu). Sxc- function is particularly critical in the CNS, as it mediates the uptake of a vital sulfu-containing amino acid needed for glutathione (GSH) synthesis and oxidative protection, while simultaneously producing an efflux of an excitatory neurotransmitter well known for its contributions to fast and slow synaptic signaling, synaptic plasticity and excitotoxic pathology. Emerging evidence also indicates that changes in SxC- activity are associated with the underlying pathological mechanisms of a variety of CNS disorders, the most prominent of which are glial brain tumors and drug addiction/relapse. Unfortunately, our growing appreciation for the functional significance of Sxc- in the CNS has rapidly outpaced the availability of potent and selective small molecules with which to modulate transporter activity. Recent synthetic and SAR-based pharmacological studies in our group have identified a novel series of potent noncompetitive inhibitors of Sxc- that we hypothesize are interacting with at least two distinct lipophilic domains adjacent to the substrate binding site on the transporter. Our identification of this new class of noncompetitive inhibitors and, consequently, a previously unrecognized binding site that can allosterically modulate transporter activity, provides an entirely new opportunity for inhibitor development. Using iterative cycles of synthesis and pharmacological assessment, linked by pharmacophore modeling, we propose to build on our lead compounds and optimize the potency and specificity of these Sxc- inhibitors. The proposed synthetic and pharmacological studies address a significant unmet need in the development of small molecules with which to probe the function of Sxc-, as well as its potential as a therapeutic target.