Targeted Library Synthesis and Screening: Allosteric Modulators of Transporters

靶向文库合成和筛选：转运蛋白的变构调节剂

基本信息

批准号：
8116614
负责人：
SUBRAMANIAM ANANTHAN
金额：
$ 37.44万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116614
关键词：
Allosteric Site Amphetamines Anxiety Benzodiazepines Binding Binding Sites Biogenic Amines Biological Biological Assay Biological Availability Blood - brain barrier anatomy Brain Cells Characteristics Chemistry Cocaine Data Development Discrimination Disease Dopamine Dose Drug Addiction Drug Kinetics Evaluation G-Protein-Coupled Receptors Goals Health Healthcare Systems Housing Human Cloning In Vitro Individual Ion Channel Knowledge Label Laboratories Lead Libraries Ligands Membrane Mental Depression Mental disorders Methamphetamine Methods Microdialysis Modeling Molecular Probes Monkeys Motor Activity Neuraxis Obsessive-Compulsive Disorder Penetration Personal Satisfaction Pharmaceutical Chemistry Pharmaceutical Preparations Phase Play Property Protocols documentation Public Health Quantitative Structure-Activity Relationship Quinazolines Radiolabeled Rattus Research Screening procedure Self Administration Self Stimulation Series Serotonin Site Societies Source Staging Structure Structure-Activity Relationship Substance abuse problem Therapeutic Variant absorption addiction analog base design dopamine transporter drug of abuse effective therapy expectation extracellular improved in vivo insight interest iterative design lead series meetings model development neuropsychiatry noradrenaline transporter novel novel strategies novel therapeutic intervention psychostimulant radioligand radiotracer receptor receptor function research study response scale up serotonin transporter small molecule success tool trend uptake

项目摘要

DESCRIPTION (provided by applicant): Discovery of ligands that modulate receptor function by binding to allosteric sites on biological targets has emerged as a promising new approach for finding drugs possessing significant therapeutic advantages over drugs that act as orthosteric ligands. Such allosteric modulators are currently being explored in-depth in the field of G-protein-coupled receptors. Among the membrane bound targets in the central nervous system, the biogenic amine transporters in general, and the dopamine (DA) transporter (DAT) in particular, play a key role in addiction to stimulant drugs of abuse and in a number of psychiatric illnesses. Although ligands that are allosteric modulators of DAT have been of considerable interest, discovery of such allosteric modulators of DAT has hitherto remained elusive. Our recent discovery of allosteric modulatory effects among a series of drug-like small molecules represents a significant breakthrough in the search for allosteric ligands of DAT. Studies with these ligands have shown that they partially inhibit DAT binding, [3H]DA uptake, and D- amphetamine induced DA release. Moreover, evaluation of a few analogues of these compounds has revealed emerging structure-activity relationship (SAR) trends among the congeners, thus setting the stage for further research on allosteric modulators of DAT function. Our goals are to pursue these initial leads to identify ligands with improved potency and endowed with favorable physicochemical properties for their use as in vitro and in vivo tools to study the biological consequences of allosteric modulation of DAT function in health and disease. Our specific aims in the R21 phase include iterative design, procurement and synthesis and evaluation of focused libraries of compounds to rapidly identify a set of ligands suitable for in vivo studies in the R33 phase. SAR analysis and QSAR model development will be utilized to pursue ligand-structure based approaches for the rational design of new focused libraries. Selected promising ligands will be evaluated against serotonin transporter (SERT) and norepinephrine transporter (NET) to ascertain their transporter target selectivity. Our expectations are that by the end of the two year R21 phase we will have identified a select set of compounds with sufficient potency, efficacy and selectivity for further studies to be performed in the next phase. The specific aims to be pursued in the R33 phase include (a) profiling the compounds against a panel of targets, (b) determination of systemic bioavailability and brain penetration properties, and (c) design and synthesis of radiolabels to serve as tools for characterizing the novel binding site. Envisioned in vivo studies with candidate molecules include (i) microdialysis experiments in rats (ii) locomotor studies in rats and (iii) determination of the effects of the compounds alone or in combination with cocaine in (1) discrimination assays in rats and monkeys, (2) intracranial self-stimulation assays in rats, and (3) self-administration studies in monkeys. These studies should reveal the potential of the allosteric ligands of DAT as treatment agents for substance abuse and psychiatric disorders.

描述（由申请人提供）：发现通过在生物靶标上与变构位点结合来调节受体功能的配体，已经成为一种有希望的新方法，用于寻找具有与起源配体的药物具有显着治疗优势的药物。这种变构调节剂目前正在G蛋白偶联受体领域进行深入探讨。在中枢神经系统中的膜结合靶标，尤其是多巴胺（DA）转运蛋白（DAT）的膜结合靶标中，在成瘾中对刺激性滥用药物和许多精神病疾病的成瘾中起着关键作用。尽管是DAT的变构调节子的配体引起了人们的关注，但迄今为止，这种变构调节剂的发现仍然难以捉摸。我们最近在一系列类似药物的小分子中发现了变构调节作用，这在寻找DAT的变构配体方面取得了重大突破。使用这些配体的研究表明，它们部分抑制了DAT结合，[3H] DA摄取和D-苯丙胺诱导的DA释放。此外，对这些化合物的一些类似物的评估揭示了同类物之间的新兴结构 - 活性关系（SAR）趋势，因此为进一步研究DAT功能的变构调节剂奠定了基础。我们的目标是追求这些最初的潜在线索，以识别具有提高效力的配体，并具有有利的物理化学特性，以用作体外和体内工具，以研究健康和疾病中DAT功能的生物学调节的生物学后果。我们在R21阶段的具体目的包括迭代设计，采购和合成以及对化合物的聚焦文库进行评估，以迅速识别一组适合R33阶段体内研究的配体。 SAR Analysis和QSAR模型开发将用于采用基于配体结构的方法，用于新的重点库的理性设计。选定的有希望的配体将对5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）进行评估，以确定其转运蛋白靶标选择性。我们的期望是，在两年R21阶段结束时，我们将确定一组具有足够效力，功效和选择性的化合物，以便在下一阶段进行进一步的研究。在R33阶段要追求的具体目的包括（a）针对靶标小组的化合物进行分析，（b）确定系统性生物可用性和脑穿透性特性，以及（c）放射性标记的设计和合成以作为表征新颖结合位点的工具。 Envisioned in vivo studies with candidate molecules include (i) microdialysis experiments in rats (ii) locomotor studies in rats and (iii) determination of the effects of the compounds alone or in combination with cocaine in (1) discrimination assays in rats and monkeys, (2) intracranial self-stimulation assays in rats, and (3) self-administration studies in monkeys.这些研究应揭示DAT的变构配体作为治疗剂滥用药物和精神疾病的潜力。