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Neuroleptic Spacer Length Governs Molecular Recognition

抗精神病药间隔基长度控制分子识别

基本信息

批准号：
7829979
负责人：
JOHN A SCHETZ
金额：
$ 7.84万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-14 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7829979
关键词：
Accounting Affect Affinity Agonist Amino Acids Antipsychotic Agents Aromatic Amino Acids Attention deficit hyperactivity disorder Binding Clozapine Cysteine Data Disease Docking Dopamine Dopamine D2 Receptor Dopamine Receptor Drug usage Electrostatics Elements G-Protein-Coupled Receptors Hydrogen Bonding Imidazole Investigation Length Leucine Ligand Binding Ligands Measures Membrane Membrane Lipids Modeling Molecular Molecular Models Morphologic artifacts Mutation Outcome Pharmaceutical Preparations Phenotype Phenylalanine Piperazines Point Mutation Positioning Attribute Property Protein Conformation Protocols documentation Receptor Activation Relative (related person)Research Personnel Rhodopsin Risperidone Series Specific qualifier value Structure Study models System Techniques Testing Therapeutic Agents Tryptophan Work base comparative efficacy design dopamine D4 receptor functional outcomes insight molecular modeling molecular recognition molecular site mutant neuropsychiatry preference prevent programs protein misfolding quetiapine receptor

项目摘要

DESCRIPTION (provided by applicant): The broad objective of this proposal is to identify and characterize the most critical molecular sites of interaction between drugs with antipsychotic activity, or potential anti-attention deficit hyperactivity disorder (ADHD) activity, and their G protein-coupled receptor (GPCR) targets. We aim to achieve an understanding of the molecular mechanisms of selective activation by agonists, and inactivation by inverse agonists, as well as the discriminant structural features of neutral antagonists that selectively bind to the D2 and D4 receptors and that are the targets for the drugs used to treat neuropsychiatric disorders. To achieve these objectives, molecular modeling techniques have been employed to predict receptor microdomains that might be interacting with selective and nonselective agonists and antagonists that were docked into rhodopsin-based models of dopamine D2 and D4 receptors. The inferences from these models will be probed with point mutations of the receptor microdomains that appear to be responsible for the functional interactions. In iterative studies, the binding and functional properties of the ligands will be determined in combinedcomputational and experimental protocols to test specific structure-based hypotheses in the mutant and wild type receptor constructs and to relate them to functional outcomes. The results will be interpreted as useful guides for the design of new putative therapeutic agents. The proposed studies will proceed as described in the following series of four interrelated specific aims: 1.) to utilize structural information about high affinity ligands in the structural context ofrhodopsin-based models for dopamine D2 and D4 GPCRs, in order to discriminate receptor microdomains and modes of ligand binding in relation to the agonist versus the antagonist activity of the ligands, 2.) to characterize the manner in which the structures of the ligands relate totheir ability to activate or inactivate dopamine D2 and D4 receptors based on different modes of binding and interaction within identified receptor microdomains, 3.) to determine if certain aromatic 1,4-disubstitutedpiperizine ligands that share an extraordinarily high selectivity for the D4 subtype of dopamine receptor are interacting with a common set of receptor microdomains, and 4.) to apply the combination of molecular models of ligand interaction in dopaminc receptor microdomains and modes of receptor activation, with experimental testing to probe new ligands predicted to have specified effects on D2 and D4 receptors.

描述（由申请人提供）：本提案的主要目标是确定和表征具有抗精神病活性或潜在的抗注意缺陷多动障碍（ADHD）活性的药物及其G蛋白偶联受体（GPCR）靶点之间相互作用的最关键分子位点。我们的目标是了解激动剂选择性激活和逆激动剂失活的分子机制，以及选择性结合D2和D4受体的中性拮抗剂的区别结构特征，这些受体是用于治疗神经精神疾病的药物的靶点。为了实现这些目标，分子建模技术已经被用于预测受体微域，这些微域可能与选择性和非选择性激动剂和拮抗剂相互作用，这些受体微域被停靠在基于视紫红质的多巴胺D2和D4受体模型中。从这些模型的推论将与受体微域的点突变进行探讨，这些突变似乎负责功能相互作用。在迭代研究中，将结合计算和实验方案确定配体的结合和功能特性，以测试突变型和野生型受体构建中特定的基于结构的假设，并将其与功能结果联系起来。这些结果将被解释为设计新的假定治疗剂的有用指南。拟议的研究将按照以下四个相互关联的具体目标进行：1)在基于视紫红质的多巴胺D2和D4 gpcr模型的结构背景下，利用高亲和力配体的结构信息，以区分与配体的激动剂和拮抗剂活性相关的受体微域和配体结合模式；2)表征这些配体的结构与其激活或灭活多巴胺D2和D4受体的能力相关的方式，这是基于在已识别的受体微域内不同的结合和相互作用模式，3)确定某些对多巴胺受体D4亚型具有极高选择性的芳香1,4-二取代哌嗪配体是否与一组共同的受体微域相互作用。4)将多巴胺受体微域中配体相互作用的分子模型与受体激活模式相结合，通过实验检测来探测预计对D2和D4受体具有特定作用的新配体。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones.

DOI：
10.1016/j.ejphar.2007.09.020
发表时间：
2008-01
期刊：
European journal of pharmacology
影响因子：
5
作者：
Ivan Lee;Shiuhwei Chen;J. Schetz
通讯作者：
Ivan Lee;Shiuhwei Chen;J. Schetz

Design, synthesis, radiolabeling, and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a potential positron emission tomography tracer for the dopamine D(4) receptors.

DOI：
10.1021/jm100925m
发表时间：
2010-10-28
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Lacivita E;De Giorgio P;Lee IT;Rodeheaver SI;Weiss BA;Fracasso C;Caccia S;Berardi F;Perrone R;Zhang MR;Maeda J;Higuchi M;Suhara T;Schetz JA;Leopoldo M
通讯作者：
Leopoldo M

Protein expression in the Drosophila Schneider 2 cell system.

果蝇 Schneider 2 细胞系统中的蛋白质表达。