Novel Methods to Identify Targets of the Neurological Agent (R)-Lacosamide

识别神经药物 (R)-拉科酰胺靶点的新方法

• 批准号: 7643122
• 负责人: HAROLD Lewis KOHN
• 金额: $ 31.75万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643122
• 关键词: Address; Adverse effects; Affect; Affinity; Amino Acids; Animals; Anticonvulsants; Antiepileptic Agents; Behavioral; Binding; Binding Sites; Biological Assay; Biology; Brain; CCL4 gene; Cells; Chemicals; Chemistry; Child; Clinical; Clinical Research; Clinical Treatment; Complex Regional Pain Syndromes; Development; Diabetic Neuropathies; Disease; Dizziness; Drowsiness; Electrophysiology (science); Epilepsy; Europe; Focal Seizure; Frequencies; Functional disorder; In Vitro; Individual; Lead; Ligands; Liver; Malignant Neoplasms; Messenger RNA; Methods; Modeling; Molecular; Molecular Probes; Molecular Target; Molecular Weight; Mus; Nausea; Nervous system structure; Neurologic; Neurons; New Agents; Pain; Pain management; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase III Clinical Trials; Population; Postherpetic neuralgia; Proteins; Protocols documentation; Public Health; Quality of life; Recurrence; Rehabilitation therapy; Reporter; Reporting; Seizures; Series; Site; Societies; Specificity; Structure; Syndrome; Techniques; Technology; Therapeutic; Toxic effect; Treatment Protocols; United States; analog; base; chronic pain; cost; design; disability; experience; molecular site; nervous system disorder; neuropsychological; novel; painful neuropathy; prevent; radioligand; receptor; tool

DESCRIPTION (provided by applicant): Epilepsy and neuropathic pain are major neurological disorders that affect all populations. Pharmacological and clinical studies document the similarities in the pathophysiological phenomena observed in epilepsy and neuropathic pain, and thus an increasing number of seizure medications are used for both disorders. Unfortunately, many patients continue to have seizures and experience pain while others experience disturbing side-effects. There is a need, therefore, for new, efficacious agents that target novel neurological pathways for these disorders. (R)-Lacosamide ((R)-2) is a simple, stereospecific agent that we discovered in 1992; it has entered phase III clinical trials for the treatment of partial seizures and diabetic neuropathy in the United States and Europe. The pharmacological profile for (R)-2 is distinct from all established antiepileptic agents. Preliminary pharmacological studies indicate that (R)-2 exerts its activity by multiple pathways. Efforts (e.g., electrophysiology, radioligand displacement assays) to identify the sites of (R)-2 function have been unsuccessful. This proposal focuses on elucidating the (R)-2 binding sites in the brain. Powerful methods are employed to address this objective. We advance a series of lacosamide analogs termed affinity bait (AB), chemical receptor (CR), and affinity bait and chemical receptor (AB&CR) designed to capture and identify the targets. We couple our molecular probes with mRNA-display and affinity-based technologies to reveal (R)-2 binding sites that explicate function. The targets are characterized and validated, and the molecular sites of (R)-2 binding determined. The use of AB&CR probes with mRNA-display and affinity matrix methods as a novel tool expands the use of these technologies for ligand site identification, where binding is modest and where moderate-to- extensive ligand structural change abolishes target binding. Relevance to public health: Current medications for the treatment of epilepsy are ineffective for approximately one-third of patients. The situation is comparable for neuropathic pain management. (R)-2's pharmacological profile is novel, but its molecular targets are unknown. Delineation of these sites will provide a basis for understanding the mechanism of (R)-2 function and maximizing its therapeutic potential and may provide new information for the control of both neurological disorders.

描述（由申请人提供）：癫痫和神经性疼痛是影响所有人群的主要神经系统疾病。药理学和临床研究记录了在癫痫和神经性疼痛中观察到的病理生理现象的相似性，因此越来越多的癫痫药物用于治疗这两种疾病。不幸的是，许多患者继续出现癫痫发作和疼痛，而另一些患者则出现令人不安的副作用。因此，需要针对这些疾病的新神经通路的新的、有效的药物。 (R)-拉科酰胺 ((R)-2) 是我们于 1992 年发现的一种简单的立体特异性药物；它已在美国和欧洲进入治疗部分性癫痫发作和糖尿病神经病变的 III 期临床试验。 (R)-2 的药理学特征与所有已确定的抗癫痫药不同。初步药理学研究表明(R)-2通过多种途径发挥其活性。鉴定 (R)-2 功能位点的努力（例如电生理学、放射性配体置换测定）尚未成功。该提案的重点是阐明大脑中的 (R)-2 结合位点。采用强有力的方法来实现这一目标。我们开发了一系列拉科酰胺类似物，称为亲和诱饵 (AB)、化学受体 (CR) 以及亲和诱饵和化学受体 (AB&CR)，旨在捕获和识别目标。我们将分子探针与 mRNA 展示和基于亲和力的技术结合起来，以揭示可阐明功能的 (R)-2 结合位点。对目标进行表征和验证，并确定 (R)-2 结合的分子位点。使用带有 mRNA 展示和亲和矩阵方法的 AB&CR 探针作为一种新工具，扩展了这些技术在配体位点识别中的用途，其中结合是适度的，并且中度至广泛的配体结构变化消除了靶标结合。与公共卫生的相关性：目前治疗癫痫的药物对大约三分之一的患者无效。神经病理性疼痛的情况与此类似。 (R)-2 的药理学特征是新颖的，但其分子靶点尚不清楚。这些位点的描绘将为理解 (R)-2 功能机制和最大限度地发挥其治疗潜力提供基础，并可能为控制这两种神经系统疾病提供新信息。

项目成果

Merging the structural motifs of functionalized amino acids and alpha-aminoamides: compounds with significant anticonvulsant activities.

合并功能化氨基酸和 α-氨基酰胺的结构基序：具有显着抗惊厥活性的化合物。

• DOI: 10.1021/jm100185c
• 发表时间: 2010
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Salome,Christophe;Salome-Grosjean,Elise;Stables,JamesP;Kohn,Harold
• 通讯作者: Kohn,Harold

Identification of a lacosamide binding protein using an affinity bait and chemical reporter strategy: 14-3-3 ζ.

• DOI: 10.1021/ja2034156
• 发表时间: 2011-07-27
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Park, Ki Duk;Kim, Dongwook;Reamtong, Onrapak;Eyers, Claire;Gaskell, Simon J.;Liu, Rihe;Kohn, Harold
• 通讯作者: Kohn, Harold

Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group.

蛋白质组学搜索比较两种 (R)-拉科酰胺亲和诱饵：亲电子芳基异硫氰酸酯和光活化芳基叠氮化物基团。

• DOI: 10.1039/c000987c
• 发表时间: 2010
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Park,KiDuk;Stables,JamesP;Liu,Rihe;Kohn,Harold
• 通讯作者: Kohn,Harold

Lacosamide isothiocyanate-based agents: novel agents to target and identify lacosamide receptors.

拉科酰胺异硫氰酸酯类药物：靶向和识别拉科酰胺受体的新型药物。

• DOI: 10.1021/jm9012054
• 发表时间: 2009
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Park,KiDuk;Morieux,Pierre;Salomé,Christophe;Cotten,StevenW;Reamtong,Onrapak;Eyers,Claire;Gaskell,SimonJ;Stables,JamesP;Liu,Rihe;Kohn,Harold
• 通讯作者: Kohn,Harold

Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage-gated sodium channels.

抗癫痫药物拉科酰胺新型衍生物的开发和表征，其对电压门控钠通道的缓慢失活表现出更大的增强作用。

• DOI: 10.1021/cn100089b
• 发表时间: 2011
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Wang,Yuying;Park,KiDuk;Salome,Christophe;Wilson,SarahM;Stables,JamesP;Liu,Rihe;Khanna,Rajesh;Kohn,Harold
• 通讯作者: Kohn,Harold