Selective CB2 Cannabinoid Agonists as Candidate Therapeutics for ALS

项目摘要： 肌萎缩侧索硬化症（ALS）是一种以进行性硬化为特征的神经退行性疾病， 运动神经元丧失、瘫痪和2 - 5年内死亡。目前，没有有效的 存在用于治疗这种毁灭性疾病的药物。神经炎症 可能极大地影响ALS期间运动神经元损失的进展。大麻素产生 通过CB 1和CB 2受体发挥抗炎作用，并延缓病理性 以神经炎症为特征的病症。在G93 A-SOD 1（G93 A）突变小鼠中， 在ALS的良好表征的动物模型中，我们证明了mRNA、受体结合和 CB 2受体的功能，而不是CB 1，在脊髓中显著地和选择性地上调。 G93 A小鼠的脐带以与疾病进展密切平行的时间模式。更 重要的是，每天注射两种结构不同的选择性CB 2激动剂（AM-1241和L-1242）， 759，633）在症状发作时开始，显著维持运动功能并增加存活率 发病后间隔时间。因此，我们认为选择性CB 2激动剂可能代表 一种治疗ALS的新方法虽然CB 2激动剂可能对这种毁灭性的疾病有用 神经退行性疾病，它们作为药剂的发展已经从根本上 这受到它们在水性或其它生物相容性载体中的相对不溶性的阻碍。事实上， 证据表明，AM-1241的实际最大功效可能是 由于在我们的初步研究中采用的载体的药物递送低于最佳， 问题研究因此，我们建议需要进行药代动力学研究，以确定 产生最大功效所需的有效媒介物、给药途径和/或剂量 G93 A小鼠中的AM-1241。此R21应用程序的当前A1版本将“确定候选 治疗”和“获得关于候选治疗的功效的初步数据”， 进行以下两个具体目标：具体目标1将确定新的CB 2激动剂， 通过筛选一系列基于吲哚和经典大麻素的ALS候选治疗剂， CB 2激动剂由John W.霍夫曼（克莱姆森大学，SC）为他们的能力，减缓 疾病进展和延长G93 A小鼠的存活。具体目标2将优化 AM-1241的治疗潜力，一种在G93 A小鼠模型中证明有效的CB 2激动剂， 人症这将通过使用给药溶剂和给药途径来实现 通过药代动力学研究证明，可将AM-1241最大程度地递送至血清 和脊髓。该项目确定的选择性CB 2激动剂可能是第一个有效的 治疗ALS的药物。最重要的是，我们的长期目标是将成果转化为 这些研究将用于未来ALS患者的临床试验。项目叙述： 肌萎缩侧索硬化症（ALS）是一种以进行性硬化为特征的神经退行性疾病， 运动神经元丧失、瘫痪和2 - 5年内死亡。目前，没有有效的 存在治疗这种毁灭性疾病的药物。基于一些令人兴奋的初步证据 证据，该项目将寻求发现新的药物称为“CB 2激动剂”，这可能是第一个 延长ALS患者生命的一类有效药物。

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.