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在癫痫和神经性疼痛中观察到的病理生理学现象的相似性，因此越来越多的癫痫发作药物用于这两种疾病。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，需要靶向这些疾病的新神经通路的新的有效药剂。（R）-Lacosamide（（R）-2）是我们在1992年发现的一种简单的立体特异性药物;它已进入美国和欧洲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的药理学特征不同于所有已建立的抗癫痫药。初步药理学研究表明，（R）-2通过多种途径发挥其活性。努力（例如，电生理学、放射性配体置换测定）来鉴定（R）-2功能的位点一直不成功。该提议的重点是阐明脑中的（R）-2结合位点。为实现这一目标，采用了强有力的方法。我们提出了一系列的拉考沙胺类似物称为亲和诱饵（AB），化学受体（CR），亲和诱饵和化学受体（AB&CR）设计用于捕获和识别的目标。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（R）-2结合位点，从而阐明功能。对靶标进行表征和验证，并确定（R）-2结合的分子位点。使用AB&CR探针与mRNA展示和亲和矩阵方法作为一种新的工具，扩展了这些技术用于配体位点识别的用途，其中结合是适度的，并且其中中度到广泛的配体结构变化消除了靶结合。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管理相当。(R)-2的药理学特征是新颖的，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.