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

• 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
• 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

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(申请人提供)：精神分裂症是一种慢性神经疾病，影响约1%的世界人口，仅在美国就造成600亿美元的直接和间接社会成本(Wu等人，2005年)。目前治疗这种疾病的方法 在改善阳性症状(幻觉、妄想、非理性恐惧)方面有效， 但在控制消极症状(社交退缩、快感缺乏)和认知功能障碍(学习和社会认知能力下降)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。由于目前的药物无法控制一系列症状，精神分裂症仍然是一个严重的医学问题，需要确定替代药物干预的目标。谷氨酸受体功能低下是为了更全面地了解和治疗精神分裂症而出现的一种假说。这一假说最初是基于观察到N-甲基-D-天冬氨酸(NMDA)受体通道阻滞剂(如苯环利定(PCP))可以在人和动物模型中诱导与精神分裂症的某些特征难以区分的心理状态。因此，NMDA受体功能的增强已成为治疗精神分裂症的一个有吸引力的假说。最近发现了一种小分子化合物(3-chlorophenyl)(6，7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3，4-dihydroisoquinolin-2(1 H-基)甲酮，它能选择性地增强含有NMDA受体的GluN2C和GluN2D受体2倍。GluN2C和GluN2D亚基是特别感兴趣的靶点，因为它们在前脑中的表达谱是 这主要局限于海马区和大脑皮层中间神经元的一个子集，精神分裂症的基于电路的模型预测，由GluN2C/2D选择性增强剂驱动的中间神经元活性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的GluN2C/2D选择性增强剂，用于精神分裂症的抗精神病药物治疗。 公共卫生相关性：精神分裂症是一种使人虚弱的精神疾病，影响着数百万美国人。目前治疗精神分裂症的药物只有部分改善，而且往往有严重的副作用。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。