Selective CB2 Cannabinoid Agonists as Candidate Therapeutics for ALS

描述（由申请人提供）：项目概述：肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是在诊断后2至5年内进行性运动神经元丢失、瘫痪和死亡。目前，没有有效的药理学试剂存在用于治疗这种毁灭性疾病。神经炎症可能极大地影响ALS期间运动神经元损失的进展。大麻素通过CB 1和CB 2受体产生抗炎作用，并延迟以神经炎症为特征的病理状况的进展。在G93 A-SOD 1（G93 A）突变小鼠，最好的ALS动物模型，我们证明，mRNA，受体结合和功能的CB 2，但不是CB 1，受体显着和选择性上调G93 A小鼠的脊髓中的时间模式密切平行于疾病的进展。更重要的是，在症状发作时开始每日注射两种结构不同的选择性CB 2激动剂（AM-1241和L-759，633），显著维持运动功能并增加疾病发作后的存活间隔。因此，我们建议选择性CB 2激动剂可能代表ALS的一种新的治疗方式。虽然CB 2激动剂可证明对这种破坏性神经变性疾病有用，但它们作为药剂的开发从根本上受到它们在水性或其他生物相容性媒介物中的相对不溶性的阻碍。事实上，一些证据表明，AM-1241的实际最大功效可能被低估，这是由于我们的初步研究中采用的载体的药物递送不理想。因此，我们建议需要进行药代动力学研究，以确定在G93 A小鼠中产生AM-1241最大疗效所需的最有效媒介物、给药途径和/或剂量。本R21申请的当前A1版本将通过进行以下两个特定目标来“识别候选治疗剂”和“获得候选治疗剂疗效的初步数据”：特定目标1将通过筛选一系列基于吲哚和经典大麻素的CB 2激动剂来识别新型CB 2激动剂作为ALS的候选治疗剂。霍夫曼（克莱姆森大学，SC），因为他们能够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，AM-1241是一种CB 2激动剂，在ALS的G93 A小鼠模型中具有已证实的疗效。这将通过采用药代动力学研究证明的溶剂和给药途径来实现，以产生AM-1241向血清和脊髓的最大递送。该项目确定的选择性CB 2激动剂可能是治疗ALS的第一种有效药物。最重要的是，我们的长期目标是将这些研究的结果转化为未来ALS患者的临床试验。项目叙述：肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征在于在诊断后2至5年内进行性运动神经元丧失、瘫痪和死亡。目前，还没有有效的药物来治疗这种毁灭性的疾病。基于一些令人兴奋的初步证据，该项目将寻求发现称为“CB 2激动剂”的新药，这些药物可能是延长ALS患者生命的第一类有效药物。

DESCRIPTION (provided by applicant): 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.