Group II mGluR antagonists and negative modulators in depression

II 组 mGluR 拮抗剂和负调节剂治疗抑郁症

基本信息

批准号：
8703789
负责人：
Nicholas David Cosford
金额：
$ 85.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2010-09-22 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703789
关键词：
ABCB1 gene Abbreviations Address Adrenergic Agents Adverse effects Affect Analysis of Variance Anhedonia Animal Model Antidepressive Agents Artificial Membranes Behavioral Biological Assay Blood Blood - brain barrier anatomy Brain California Cerebrospinal Fluid Chronic Data Development Disease Drug Kinetics Excitatory Amino Acid Antagonists Excretory function Exhibits Future G-Protein-Coupled Receptors GABA Receptor GTP-Binding Proteins General Population Glutamate Receptor In Vitro Incidence Institutes Intellectual Property Interdisciplinary Study Isoxazoles Lead Letters Major Depressive Disorder Measures Medical Mental Depression Mental disorders Metabolism Metabotropic Glutamate Receptors Modeling Molecular Target Muscarinics NIH Program Announcements National Institute of Mental Health Neuraxis Nucleus Accumbens Opiates Peptide Receptor Pharmaceutical Preparations Phencyclidine Phenotype Population Potassium Preclinical Drug Evaluation Preclinical Testing Prevention Property Propionates Psychotropic Drugs Public Health Publications Quinoxalines Rattus Research Rewards Selective Serotonin Reuptake Inhibitor Self Stimulation Stimulus Stress Structure-Activity Relationship Swimming Testing Universities Work absorption adrenergic design drug abuser drug candidate drug development drug discovery drug metabolism high throughput screening in vitro Assay in vivo innovation interest metabotropic glutamate receptor 2 metabotropic glutamate receptor 3 metabotropic glutamate receptor 4 metabotropic glutamate receptor 7 metabotropic glutamate receptor 8 nervous system disorder novel pleasure prepulse inhibition programs public health relevance response social

项目摘要

DESCRIPTION (provided by applicant): Depression is a serious psychiatric disorder that remains a major public health problem. Approximately 21% of the general population suffers from depression sometime in their lifetime, while the incidence of depression is 30-37% in drug abusers. There has not been development of new antidepressants with novel pharmacological mechanisms of action for several decades. Recent publications and preliminary data reviewed in this application suggest that antagonists or negative allosteric modulators at metabotropic glutamate receptors (mGluR) Group II (mGluR2 and mGluR3) may have antidepressant properties. Thus, mGluR2/3 are novel targets for antidepressant treatment. This new revised R01 application is in response to PAR-07-048 entitled "Drug Discovery for Nervous System Disorders" that encourages the synthesis and "preclinical testing of novel compounds for the prevention and treatment of nervous system disorders". A multidisciplinary research team comprised of chemists (Burnham Institute), in vitro pharmacologists (Vanderbilt University) and behavioral pharmacologists (University of California, San Diego) will focus on the synthesis and testing of new mGluR2/3 orthosteric antagonists and negative allosteric modulators as treatments for depression. Specific Aim 1 will involve the design and synthesis of novel mGluR2/3 orthosteric antagonists and negative allosteric modulators with optimized potency, selectivity, and in vivo activity. Specific Aim 2 will: i) evaluate and characterize the newly synthesized compounds for potency and efficacy at mGluR2, mGluR3, other mGluRs and various other central nervous system molecular targets, and ii) perform absorption, distribution, metabolism and excretion analyses, as well as evaluate blood brain barrier permeation and pharmacokinetics using in vitro and in vivo assays. Once the optimal mGluR2/3 compounds are identified (see Research Plan for criteria used to select compounds), Specific Aim 3 will investigate the effects of these selected compounds in animal models of: i) stress-induced anhedonia involving assessment of elevations in intracranial self-stimulation (ICSS) reward thresholds after chronic social defeat in rats; and ii) antidepressant-like activity in the forced swim test in rats. Anhedonia is defined as diminished interest or pleasure in rewarding stimuli and is considered a core behavioral phenotype of depression. Thus, compounds with demonstrated anti-anhedonic activity in the stress- induced anhedonia model or antidepressant-like activity in the forced swim test and which also exhibit drug-like properties will be considered putative drug candidates for future drug discovery and development efforts. Potential side-effects will be assessed in later years of the project, once drug-like candidates are identified. The proposed multidisciplinary research program is highly significant as it addresses an important public health problem, innovative as it focuses on Group II mGluRs as targets for novel antidepressants, and timely as it is in response to a Program Announcement by NIH. Therefore, this research program has the potential for a significant scientific and medical impact by contributing to the discovery of new medications for depression. PUBLIC HEALTH RELEVANCE: Depression is a serious psychiatric disorder that affects a large percentage of the USA population. The proposed project will synthesize new compounds that will target metabotropic glutamate receptors in the brain and evaluate them for their putative antidepressant activity in animal models of depression. This project is very innovative and promises to have a highly significant overall impact by promoting the discovery of new treatments for this devastating disorder.

描述（由申请人提供）：抑郁症是一种严重的精神疾病，仍然是一个主要的公共卫生问题。大约 21% 的普通人群在一生中的某个时候患有抑郁症，而吸毒者的抑郁症发病率为 30-37%。几十年来一直没有开发出具有新药理作用机制的新抗抑郁药。本申请中回顾的最新出版物和初步数据表明，代谢型谷氨酸受体 (mGluR) II 组（mGluR2 和 mGluR3）的拮抗剂或负变构调节剂可能具有抗抑郁特性。因此，mGluR2/3 是抗抑郁治疗的新靶点。这项新修订的 R01 申请是为了响应题为“神经系统疾病的药物发现”的 PAR-07-048，该申请鼓励合成和“用于预防和治疗神经系统疾病的新型化合物的临床前测试”。由化学家（伯纳姆研究所）、体外药理学家（范德比尔特大学）和行为药理学家（加州大学圣地亚哥分校）组成的多学科研究小组将重点合成和测试新的 mGluR2/3 正构拮抗剂和负变构调节剂作为治疗方法对于抑郁症。具体目标 1 将涉及设计和合成具有优化效力、选择性和体内活性的新型 mGluR2/3 正构拮抗剂和负变构调节剂。具体目标 2 将：i) 评估和表征新合成化合物对 mGluR2、mGluR3、其他 mGluR 和各种其他中枢神经系统分子靶标的效力和功效，ii) 进行吸收、分布、代谢和排泄分析，以及使用体外和体内测定评估血脑屏障渗透性和药代动力学。一旦确定了最佳 mGluR2/3 化合物（有关选择化合物的标准，请参阅研究计划），具体目标 3 将研究这些选定化合物在以下动物模型中的影响： i) 应激诱发的快感缺失，涉及颅内自我升高的评估-大鼠慢性社交失败后的刺激（ICSS）奖励阈值； ii) 大鼠强迫游泳试验中的抗抑郁样活性。快感缺乏被定义为对奖励刺激的兴趣或快乐减少，被认为是抑郁症的核心行为表型。因此，在应激诱发的快感缺乏模型中表现出抗快感缺乏活性或在强迫游泳测试中表现出抗抑郁样活性并且还表现出药物样特性的化合物将被认为是未来药物发现和开发工作的假定候选药物。一旦确定了类似药物的候选药物，潜在的副作用将在项目的后期进行评估。拟议的多学科研究计划具有非常重要的意义，因为它解决了一个重要的公共卫生问题，具有创新性，因为它专注于 II 类 mGluR 作为新型抗抑郁药的目标，并且及时，因为它是对 NIH 计划公告的回应。因此，该研究计划有助于发现治疗抑郁症的新药物，从而有可能产生重大的科学和医学影响。公共卫生相关性：抑郁症是一种严重的精神疾病，影响着很大一部分美国人口。拟议的项目将合成新的化合物，这些化合物将靶向大脑中的代谢型谷氨酸受体，并评估它们在抑郁症动物模型中的推定抗抑郁活性。该项目非常具有创新性，有望通过促进这种破坏性疾病的新疗法的发现来产生非常重大的总体影响。