mGluR5 Allosteric Modulators

mGluR5 变构调节剂

• 批准号: 8148532
• 负责人: Amy Hauck Newman
• 金额: $ 59.02万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148532
• 关键词: Affinity; Agonist; Alkynes; Amides; Amino Acids; Animal Model; Anxiety; Area; Behavior; Binding; Binding Sites; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Calcium; Cattle; Cell Line; Cells; Central Nervous System Diseases; Cocaine; Complex; Coupled; Data; Detection; Development; Dopamine; Drug Design; Drug abuse; Ethanol; Evaluation; Family; Fluorescence; Future; G-Protein-Coupled Receptors; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Housing; Human; Hydrogen Bonding; Hydrolysis; In Vitro; Investigation; Knockout Mice; Left; Ligand Binding; Ligands; Link; Mediating; Mental Depression; Metabotropic Glutamate Receptors; Modeling; Modification; Molecular Models; Morphine; Neuraxis; Neurotransmitters; Nicotine; Nucleus Accumbens; Pain; Parents; Pathway interactions; Penetration; Pharmaceutical Preparations; Phosphatidylinositols; Phospholipase C; Positioning Attribute; Rattus; Reporting; Research Project Grants; Rewards; Rhodopsin; Role; Series; Site-Directed Mutagenesis; Structure; Structure-Activity Relationship; Synapses; System; Testing; Therapeutic Agents; Therapeutic Effect; Transmembrane Domain; Work; addiction; analog; base; design; dopamine D3 receptor; dopamine transporter; drug development; drug discovery; functional group; high throughput screening; improved; in vitro testing; in vivo; in vivo Model; molecular modeling; mouse model; nervous system disorder; novel; novel therapeutics; postsynaptic; putamen; quinoline; quinoline analog; receptor; receptor binding; stimulant abuse; tool

L-Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), which acts through the ligand-gated ionotropic glutamate receptor or through the G-protein coupled receptors (GPCR) called metabotropic glutamate receptors (mGluR). The mGluR5 belongs to the Group I subclass and is coupled to the phosphoinositide/Ca+2 pathway, which mainly mediates the excitatory effects of glutamate. Recently, investigation into the role of mGluR5 in drug abuse has led to speculation that this may be a new target for medication development. For example, studies using either an mGluR5 antagonist or mGluR5 knockout mice showed reduced locomotor stimulant effects induced by cocaine. Moreover, evidence that mGluR5 is involved in the rewarding effects of morphine, nicotine and ethanol has also been reported. Thus development of selective mGluR5 antagonists may provide a novel non-dopaminergic strategy toward the discovery of drug abuse medications. Additionally the mGluR5 has recently been implicated in anxiety and depression thus these antagonists might provide new therapeutic agents toward the treatment of these CNS disorders. In order to further explore structure-activity relationships (SAR) at mGluR5, the design and synthesis of a series of diaryl amides was initiated based on a putative ligand binding site at the transmembrane domain region of an mGluR5 molecular model, based on the bovine rhodopsin crystal structure. In vitro binding and functional evaluation at mGluR5 resulted in the discovery of several novel and moderately high affinity mGluR5 antagonists. Additional modifications of these amide-linked molecules focused on inducing an intramolecular hydrogen bond that might provide co-planarity achieved in the parent compound MPEP. Within this new series of compounds, several analogues showed moderate affinity for mGluR5, but a better design in which co-planarity could be achieved through a quinoline group was pursued. In this first group of quinoline analogues, clues to improve binding affinity at mGluR5 were revealed. In addition, synthesis of additional alkyne and amide analogues have been achieved to further explore SAR of the pendant aryl ring and then to combine these features with the quinoline structure. A large series (>250 compounds) have now been evaluated for in vitro binding and function at mGluR5 and several candidates are being evaluated in animal models of anxiety. In addition, we have discovered that although the alkyne series has provided important guidance in our drug design of the amide and quinoline series, there are significant differences in which substitution is well-tolerated in the alkyne series but not in the other two templates. Recently we have developed a customized mGluR binding assay using 3HMPEP in rat brain, a calcium fluorescence functional assay in mGluR5 transfected HEK 293 cells and several in vivo models of anxiety, a hallmark behavior associated with mGluR5 antagonism, as well as models of addiction. This work is directed to understanding the role of mGluR5 in anxiety, drug abuse and addiction and to develop potential therapeutic agents for treatment. Nevertheless, it is known that mGluR5 heterodimerizes in cells, with dopamine (DA) D2 and A2A receptors and these heterodimeric complexes may be involved in the behaviors elicited by these agents. Hence, we plan to investigate the mGluR5-D2 heteromer and further, attempt to discover if mGluR5 also forms heteromers with dopamine D3 receptors. In order to elucidate mechanistic underpinnings of the potential therapeutic effects of these mGluR5 antagonists, we propose to develop cell lines that are transfected with these heteromeric complexes. We plan to screen the 200+ compounds generated in our lab, compare these data to the data obtained in the mGluR5 transfected cells and 1) draw conclusions of overlapping structure-activity relationships (SAR) or 2) observe significant differences in SAR suggesting that these complexes produce binding domains that differ from the homomeric receptor and might be a target for new drug discovery. Finally, correlation with in vivo behavior depending on what the result of these in vitro tests will be a future goal of this project.

L-谷氨酸是中枢神经系统（CNS）中的主要兴奋性神经递质，它通过配体门控的离子型谷氨酸受体或称为G蛋白偶联受体（GPCR）（GPCR）起作用，称为代谢性谷氨酸受体（MGLUR）。 MGLUR5属于I组亚类，并耦合到磷酸肌醇/Ca+2途径，该途径主要介导谷氨酸的兴奋作用。最近，对MGLUR5在药物滥用中的作用的调查导致人们猜测这可能是药物开发的新目标。 例如，使用MGLUR5拮抗剂或MGLUR5敲除小鼠的研究表明可卡因诱导的运动刺激作用降低。此外，还报道了MGLUR5参与吗啡，尼古丁和乙醇的奖励作用的证据。因此，选择性MGLUR5拮抗剂的开发可能会为发现药物滥用药物提供一种新型的非多巴胺能策略。另外，MGLUR5最近与焦虑和抑郁症有关，因此这些拮抗剂可能会为治疗这些中枢神经系统疾病的治疗提供新的治疗剂。 为了进一步探索MGLUR5处的结构 - 活性关系（SAR），基于牛Rhopopsin晶体结构的MGLUR5分子模型的推定配体结合位点，基于推定的MGLUR5分子模型的跨膜结构域区域的假定配体结合位点启动了一系列日记酰胺的设计和合成。 MGLUR5处的体外结合和功能评估导致发现了几种新颖和中等高亲和力MGLUR5拮抗剂。 这些酰胺连接的分子的其他修饰集中在诱导分子内氢键，该分子内氢键可能会在母体化合物MPEP中提供共同的平面度。 在这一新的化合物中，几个类似物显示出对MGLUR5的中等亲和力，但是可以通过奎诺林组实现更好的设计。 在第一组喹啉类似物中，揭示了改善MGLUR5结合亲和力的线索。 此外，已经实现了其他藻类和酰胺类似物的合成，以进一步探索吊芳环的SAR，然后将这些特征与喹啉结构相结合。 现在已经评估了一个大型系列（> 250种化合物），以在MGLUR5上进行体外结合和功能，并在焦虑动物模型中评估了几种候选物。此外，我们发现，尽管Alkyne系列在我们的酰胺和喹啉系列的药物设计中提供了重要的指导，但在Alkyne系列中替代良好的替代存在很大的差异，但在其他两个模板中却没有。 最近，我们使用3HMPEP在大鼠脑中开发了一种定制的MGLUR结合测定法，MGLUR5中的钙荧光功能分析转染了​​HEK 293细胞和几种焦虑的体内模型，这是一种与MGLUR5拮抗作用相关的标志性行为，以及成瘾模型。这项工作旨在了解MGLUR5在焦虑，药物滥用和成瘾中的作用，并开发潜在的治疗剂进行治疗。然而，众所周知，MGLUR5在细胞中异二聚二聚体，多巴胺（DA）D2和A2A受体以及这些异二聚体复合物可能与这些药物引起的行为有关。 因此，我们计划研究MGLUR5-D2异构体，然后尝试发现MGLUR5是否还形成了多巴胺D3受体的异构体。为了阐明这些MGLUR5拮抗剂的潜在治疗作用的机械基础，我们建议开发用这些异源复合物转染的细胞系。 我们计划筛选实验室中生成的200多种化合物，将这些数据与MGLUR5转染的细胞中获得的数据进行比较，1）得出重叠结构 - 活性关系（SAR）或2）的结论，在SAR中观察到显着差异，这表明这些复合物会产生与共生受体不同的结合域，这些结合域可能是差异的，这些结合域可能是针对性受体和新药物发现的目标。最后，与体内行为相关，具体取决于这些体外测试的结果将是该项目的未来目标。