Selective CB2 Cannabinoid Agonists as Candidate Therapeutics for ALS

项目总结： 肌萎缩侧索硬化症(ALS)是一种以进行性神经退行性疾病为特征的疾病 运动神经元丢失、瘫痪和在确诊后2至5年内死亡。目前，没有有效的 治疗这种毁灭性疾病的药物是存在的。神经性炎症 可能对肌萎缩侧索硬化症时运动神经元丢失的进展有很大影响。大麻素生产 CB1和CB2受体的抗炎作用与延缓病理进展 以神经炎症为特征的状况。在G93A-SOD1(G93A)突变小鼠中，大多数 在ALS的动物模型中，我们证明了mRNA、受体结合和 CB2而不是CB1受体的功能在脊髓中显著和选择性地上调 G93A小鼠的脐带在时间模式上与疾病进展密切平行。更多 重要的是，每天注射两种结构多样化的选择性CB2激动剂(AM-1241和L- 759,633)，显著维持运动功能，提高存活率 发病后的间隔时间。因此，我们认为选择性CB2激动剂可能代表 治疗肌萎缩侧索硬化症的新方法。而CB2激动剂可能被证明对这种毁灭性的 神经退行性疾病，它们作为药物的发展已经从根本上 由于它们在水中或其他生物相容的载体中相对不溶而受阻。事实上，有几个 一系列证据表明，AM-1241的实际最大药效可能是 由于我们初步使用的车辆的药物输送不够理想，所以被低估了 学习。因此，我们建议需要药代动力学研究来确定最大 产生最大药效所需的有效载体、给药路线和/或剂量 G93A小鼠AM-1241。此R21应用程序的当前A1修订版将“确定候选 治疗和获得有关ALS候选疗法疗效的初步数据 执行以下两个特定目标：特定目标1将确定新的CB2激动剂为 通过筛选一系列吲哚和经典大麻素为基础的ALS候选疗法 由John W.Huffman博士(加州大学克莱姆森分校)提供的CB2激动剂，以表彰其减缓速度的能力 延长G93A小鼠的疾病进展和生存时间。《特定目标2》将优化 已证实有效的CB2激动剂AM-1241对G93A小鼠模型的治疗潜力 肌萎缩侧索硬化。这将通过使用管理的车辆和路线来实现 药代动力学研究证明，AM-1241在血清中的释放量最大 和脊髓。该项目确定的选择性CB2激动剂可能是第一个有效的 治疗肌萎缩侧索硬化症的药物最重要的是，我们的长期目标是将结果从 这些研究将在未来对ALS患者进行临床试验。项目说明： 肌萎缩侧索硬化症(ALS)是一种以进行性神经退行性疾病为特征的疾病 运动神经元丢失、瘫痪和在确诊后2至5年内死亡。目前，没有有效的 治疗这种毁灭性疾病的药物是存在的。基于一些激动人心的初步调查 证据表明，该项目将寻求发现被称为“CB2激动剂”的新药，这可能是第一个 一类能延长ALS患者生命的有效药物。

Project Summary: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2 to 5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may greatly influence the progression of motor neuron loss during ALS. Cannabinoids produce anti-inflammatory actions via CB1 and CB2 receptors and delay the progression of pathologic conditions characterized by neuroinflammation. In G93A-SOD1 (G93A) mutant mice, the most well-characterized animal model of ALS, we demonstrate that mRNA, receptor binding and function of CB2, but not CB1, receptors are dramatically and selectively upregulated in the spinal cords of G93A mice in a temporal pattern closely paralleling disease progression. More importantly, daily injections of two structurally diverse selective CB2 agonists (AM-1241 and L- 759,633) initiated at symptom onset, markedly maintain motor function and increase the survival interval after disease onset. Therefore, we propose that selective CB2 agonists may represent a novel therapeutic modality for ALS. While CB2 agonists may prove useful for this devastating neurodegenerative disease, their development as pharmaceutical agents has been fundamentally hindered by their relative insolubility in aqueous, or other biocompatible, vehicles. Indeed, several lines of evidence indicate that the actual maximal efficacy of AM-1241 might have been underestimated due to less than optimal drug delivery by the vehicle employed in our preliminary studies. As such, we propose that pharmacokinetic studies are needed to determine the most efficient vehicle, route of administration and/or dose required to produce the maximal efficacy of AM-1241 in G93A mice. The current A1 revision of this R21 application will "identify candidate therapeutics" and "obtain preliminary data on the efficacy of candidate therapeutics" for ALS by conducting the following two Specific Aims: Specific Aim 1 will identify novel CB2 agonists as candidate therapeutics for ALS by screening a series of indole and classic cannabinoid-based CB2 agonists provided by Dr. John W. Huffman (Clemson University, SC) for their ability to slow disease progression and prolong survival of G93A mice. Specific Aim 2 will optimize the therapeutic potential of AM-1241, a CB2 agonist with proven efficacy in the G93A mouse model of ALS. This will be accomplished by employing the vehicle and route of administration demonstrated by pharmacokinetic studies to produce the greatest delivery of AM-1241 to serum and spinal cords. Selective CB2 agonists identified by this project could be the first efficacious drugs for the management of ALS. Most importantly, our long-term goal is to translate results from these studies into a future clinical trial in ALS patients. Project Narrative: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2 to 5 years of diagnosis. Currently, no effective drugs exist for the treatment of this devastating disease. Based on some exciting preliminary evidence, this project will seek to discover new drugs called "CB2 agonists" that could be the first class of effective drugs to prolong the lives of ALS patients.