Optimization of Novel NR2C and NR2D subunit-selective NMDA receptor potentiators

新型 NR2C 和 NR2D 亚基选择性 NMDA 受体增强剂的优化

基本信息

批准号：
8251245
负责人：
SCOTT James MYERS
金额：
$ 34.57万
依托单位：
NEUROP, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-03 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8251245
关键词：
Adverse effects Affect Agonist American Anhedonia Animal Model Antipsychotic Agents Binding Sites Brain Chemosensitization Chronic Cognition Delusions Development Disease Dopamine Antagonists Drug Kinetics Electrodes Fright Glutamate Agonist Glutamate Receptor Glycine Goals Hallucinations Hippocampus (Brain)Human Impaired cognition Interneurons Intervention Lead Learning Libraries Ligands Measures Medical Medicine Mental disorders Metabolic Metabolic syndrome Modeling Molecular Profiling N-Methyl-D-Aspartate Receptors N-Methylaspartate Oocytes Oral Administration Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Phencyclidine Plasma Population Property Prosencephalon Quality of life Recombinants Schizophrenia Screening procedure Site Solubility Specificity Structure-Activity Relationship Symptoms System Testing Weight Gain Withdrawal Xenopus laevis analog atypical antipsychotic base cardiovascular risk factor channel blockers cost design efficacy testing improved in vivo interest intravenous administration kainate man nervous system disorder novel prepulse inhibition psychologic receptor receptor function response serotonin receptor small molecule social social cognition tool transport inhibitor virtual voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a chronic neurological disorder that affects approximately 1% of the world population and causes > $60 billion dollars of direct and indirect societal costs in the US alone (Wu et al., 2005). Current therapies to treat this disorder have been effective in ameliorating positive symptoms (hallucinations, delusions, irrational fear), but are less effective in controlling negative symptoms (social withdrawal, anhedonia) and cognitive dysfunction (diminished learning and social cognition). Furthermore, many of the current antipsychotics can cause extrapyramidal side effects (EPS), metabolic syndrome (weight gain), and increased cardiovascular risk liabilities. Due to the inability to control the fll spectrum of symptoms with today's medicines schizophrenia remains a serious medical problem requiring the identification of alternative targets for pharmacological intervention. Glutamate receptor hypofunction has emerged as an hypothesis to more fully understand and treat schizophrenia. This hypothesis was based initially upon observations that N-methyl-D-aspartate (NMDA) receptor channel blockers such as phencyclidine (PCP) can induce a psychological state indistinguishable from some features of schizophrenia in man and in animal models. Thus, augmentation of NMDA receptor function has emerged as an attractive hypothesis as a therapy for schizophrenia. Recently, a small molecule CIQ, (3- chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1 H)-yl)methanone) was identified that selectively potentiates GluN2C and GluN2D containing NMDA receptors by 2-fold. GluN2C and GluN2D subunits are targets of particular interest in that their expression profile in forebrain is limited largely to a subset of hippocampal and cortical interneurons and that circuit-based models of schizophrenia predict that enhancement of interneuron activity driven by GluN2C/2D selective potentiators may be particularly efficacious. Based on these recent findings, we propose to discover and develop novel GluN2C/2D selective potentiators for use as antipsychotics in the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating mental illness that affects millions of Americans. Current medicines for schizophrenia provide only partial improvement and often have serious side effects. The goal of this project is to develop better medicines to improve the quality of life for schizophrenia patients.

描述（由申请人提供）：精神分裂症是一种慢性神经系统疾病，影响世界大约 1% 的人口，仅在美国就造成超过 600 亿美元的直接和间接社会成本（Wu 等，2005）。目前治疗这种疾病的疗法已有效改善阳性症状（幻觉、妄想、非理性恐惧），但在控制负面症状（社交退缩、快感缺乏）和认知功能障碍（学习和社交认知能力下降）方面效果较差。此外，目前的许多抗精神病药物可能会导致锥体外系副作用（EPS）、代谢综合征（体重增加）和心血管风险增加。由于当今的药物无法控制全部症状，精神分裂症仍然是一个严重的医学问题，需要确定药物干预的替代目标。谷氨酸受体功能减退已成为一种假说，以更全面地理解和治疗精神分裂症。这一假设最初基于这样的观察：N-甲基-D-天冬氨酸 (NMDA) 受体通道阻滞剂，如苯环己哌啶 (PCP)，可以在人和动物模型中诱发与精神分裂症的某些特征难以区分的心理状态。因此，增强 NMDA 受体功能已成为治疗精神分裂症的一个有吸引力的假设。最近，一种小分子CIQ，(3-氯苯基)(6,7-二甲氧基-1-((4-甲氧基苯氧基)甲基)-3,4-二氢异喹啉-2(1H)-基)甲酮)被鉴定出选择性地使含有 NMDA 受体的 GluN2C 和 GluN2D 增强 2 倍。 GluN2C 和 GluN2D 亚基是特别令人感兴趣的靶标，因为它们在前脑中的表达谱是主要限于海马和皮质中间神经元的一个子集，并且基于回路的精神分裂症模型预测，由 GluN2C/2D 选择性增强剂驱动的中间神经元活动的增强可能特别有效。基于这些最新发现，我们建议发现和开发新型 GluN2C/2D 选择性增强剂，用作治疗精神分裂症的抗精神病药。公共卫生相关性：精神分裂症是一种使人衰弱的精神疾病，影响着数百万美国人。目前治疗精神分裂症的药物只能部分改善，并且常常有严重的副作用。该项目的目标是开发更好的药物来改善精神分裂症患者的生活质量。