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

• 批准号: 8510615
• 负责人: SUBRAMANIAM ANANTHAN
• 金额: $ 37.6万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510615
• 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; 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; screening; serotonin transporter; small molecule; success; tool; trend; uptake

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）：发现通过与生物靶点上的变构位点结合来调节受体功能的配体已经成为一种有前途的新方法，用于发现与用作正构配体的药物相比具有显著治疗优势的药物。这种变构调节剂目前正在G蛋白偶联受体领域进行深入研究。在中枢神经系统中的膜结合靶点中，生物胺转运蛋白一般，特别是多巴胺（DA）转运蛋白（DAT），在滥用兴奋剂药物成瘾和许多精神疾病中起关键作用。尽管作为DAT的变构调节剂的配体已经引起了相当大的兴趣，但是发现这样的DAT的变构调节剂迄今为止仍然是难以捉摸的。我们最近发现的一系列药物样小分子的变构调节作用代表了在寻找DAT的变构配体方面的重大突破。这些配体的研究表明，它们部分抑制DAT结合，[3 H]DA摄取和D-苯丙胺诱导的DA释放。此外，这些化合物的一些类似物的评价揭示了同系物之间的新兴结构-活性关系（SAR）趋势，从而为进一步研究DAT功能的变构调节剂奠定了基础。我们的目标是追求这些初步的线索，以确定配体具有改善的效力，并赋予其有利的物理化学性质，用于在体外和体内的工具，研究在健康和疾病的DAT功能的变构调节的生物学后果。我们在R21阶段的具体目标包括迭代设计，采购和合成以及对化合物的集中库进行评估，以快速鉴定一组适合于R33阶段体内研究的配体。SAR分析和QSAR模型开发将用于追求基于配体结构的方法，以合理设计新的重点库。将针对5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）评价选定的有希望的配体，以确定其转运蛋白靶向选择性。我们的期望是，在两年的R21阶段结束时，我们将确定一组具有足够效力、有效性和选择性的化合物，用于下一阶段的进一步研究。在R33阶段追求的具体目标包括：（a）针对一组靶点分析化合物，（B）测定全身生物利用度和脑渗透特性，以及（c）设计和合成放射性标记，作为表征新结合位点的工具。设想的候选分子的体内研究包括（i）大鼠中的微透析实验（ii）大鼠中的运动研究和（iii）确定化合物单独或与可卡因组合在（1）大鼠和猴中的辨别测定、（2）大鼠中的颅内自我刺激测定和（3）猴中的自我给药研究中的作用。这些研究应揭示DAT的变构配体作为药物滥用和精神疾病治疗剂的潜力。