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

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癫痫和神经性疼痛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，许多患者继续癫痫发作并经历疼痛，而其他人则经历令人不安的副作用。因此，需要针对这些疾病的新神经通路开发新的、有效的药物。(R)-拉科沙胺（(R)-2）是我们在1992年发现的一种简单的立体特异性药物；该药物已在美国和欧洲进入治疗部分性癫痫和糖尿病性神经病变的III期临床试验。(R)-2的药理学特征不同于所有已建立的抗癫痫药物。初步药理研究表明(R)-2通过多种途径发挥其活性。识别(R)-2功能位点的努力（例如，电生理学，放射配位位移测定）都没有成功。本研究的重点是阐明大脑中的(R)-2结合位点。我们采用了强有力的方法来实现这一目标。我们提出了一系列lacosamide类似物，称为亲和诱饵（AB），化学受体（CR）和亲和诱饵和化学受体（AB&CR），旨在捕获和识别目标。我们将我们的分子探针与mrna展示和基于亲和力的技术相结合，以揭示解释功能的(R)-2结合位点。对这些靶点进行了表征和验证，并确定了(R)-2结合的分子位点。将AB&CR探针与mrna展示和亲和矩阵方法结合使用，作为一种新工具，扩展了这些技术在配体位点鉴定中的应用，在配体位点鉴定中，结合是适度的，在配体结构的中等到广泛变化消除了目标结合。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。这种情况与神经性疼痛的治疗相似。(R)-2的药理学特征是新的，但其分子靶点是未知的。这些位点的描述将为理解(R)-2功能的机制和最大化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的信息。

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.