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Drug Design: Glutamate Receptor Signaling

药物设计：谷氨酸受体信号传导

基本信息

批准号：
7556423
负责人：
DALE F MIERKE
金额：
$ 33.07万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7556423
关键词：
AMPA Receptors Affinity Binding Binding Sites Biological Assay Chromosome Pairing Clinical Cocaine Computer Simulation Crystallography Cyclic Peptides DLG1 gene DLG4 gene Development Drug Addiction Drug Delivery Systems Drug Design Fluorescence GluR6 kainate receptor Glutamate Receptor Glutamates Guanylate kinase Herpes zoster disease Individual Informal Social Control Intracellular Signaling Proteins Kainic Acid Receptors Lead Ligand Binding Mediating Methods Molecular Mutation N-Methyl-D-Aspartate Receptors NCOA2 gene NMDA receptor antagonist Nitric Oxide Synthase Peptides Pharmaceutical Preparations Phosphotransferases Physiological Play Proline Property Protein Kinase C Proteins Receptor Signaling Regulation Research Research Personnel Resolution Role Route SAP90 protein Scaffolding Protein Signal Transduction Specificity Structure Surface Synapses Syndrome System Therapeutic Agents Withdrawal addiction alcohol and other drug base brain-enriched GKAP desensitization design glutamate receptor interacting protein inhibitor/antagonist insight kainate molecular modeling novel peptidomimetics polyproline presynaptic density protein 95 programs protein protein interaction receptor receptor function response scaffold src Homology Domains trafficking

项目摘要

Growing evidence indicates that glutamate receptor signaling, via both AMPA/kainate and NMDA receptors, plays a mechanistic role in drug seeking responses and that addiction is a form of glutamate- dependent plasticity. Indeed, it was recently shown that repeated administration of cocaine alters the expression levels of kainate receptors during withdrawal. AMPA/kainate and NMDA receptor antagonists have potential for clinical syndromes associated with addiction to alcohol and other drugs. Although numerous subtypes of AMPA, kainate, and NMDA receptors exist, it has proven difficult to develop subtype specific antagonists largely because of their high homology. In contrast, glutamate receptor subtypes couple to different intracellular signaling cascades via different molecular scaffolding proteins, including the synaptic associated proteins (SAPs), glutamate receptor-interacting proteins (GRIPs), and proteins interacts C kinases (PICK). These proteins contain PDZ (postsynaptic density- 95/Discs large/Zona occludens-1) domains displaying various extents of receptor subtype specificity. The SAPs (e.g., SAPg0 and SAP97) are made up of five separate domains: three PDZ domains _DZ1, PDZ2, PDZ3), a src-homology 3 domain (SH3), and a guanyl kinase-like domain (GK). Intra-molecular interactions between the different domains of the SAPs have been shown to regulate function. Here we propose to develop peptides and peptidomimetics that will disrupt the inter- and intra-interactions of these molecular scaffolding proteins. We aim to structurally characterize the inter-domain interactions of sAPg0, SAP97, GRIP, and PICK using high-resolution NMR and computer simulations. Incorporating the experimentally determined structural features into detailed molecular models of these scaffolding proteins will allow for the rational design of molecular inhibitors of these interactions. Such molecules will allow for a greater understanding of the specific protein-protein interactions as well as provide a novel route for the treatment of drug addiction.

越来越多的证据表明，谷氨酸受体通过AMPA/kainate和NMDA进行信号传导