Optimizing analgesia by exploiting CB2 agonist functional selectivity

利用 CB2 激动剂功能选择性优化镇痛

• 批准号: 8531525
• 负责人: Kenneth Mackie
• 金额: $ 19.5万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531525
• 关键词: Absence of pain sensation; Adenylate Cyclase; Adverse effects; Agonist; Analgesics; Animal Model; Attenuated; Binding; Biochemical; Biological Assay; CNR1 gene; CNR2 gene; Calcium; Calcium Channel; Cell Line; Cells; Clinical; Data; Development; Dimensions; Disease; Drug Design; Employee Strikes; Equilibrium; Evaluation; Exhibits; Family; Freund' s Adjuvant; Future; G-Protein-Coupled Receptors; Goals; Human; Hyperalgesia; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Investigation; Knockout Mice; Lead; Ligands; Ligation; MAPK3 gene; Maintenance; Mediating; Microglia; Modeling; Motivation; Neuropathy; Nociception; Outcome Study; Paclitaxel; Pain; Pathway interactions; Positioning Attribute; Pre-Clinical Model; Predictive Value; Process; Property; Public Health; Publishing; Receptor Activation; Receptor Signaling; Research; Signal Pathway; Signal Transduction; Spinal nerve structure; Synaptic Transmission; Testing; Therapeutic; Traumatic Nerve Injury; Treatment Efficacy; Work; allodynia; base; chemotherapeutic agent; chronic pain; in vitro Assay; inflammatory neuropathic pain; inflammatory pain; insight; member; migration; neutrophil; pain behavior; painful neuropathy; pre-clinical; public health relevance; receptor; receptor internalization; research study; trafficking

DESCRIPTION (provided by applicant): This is a proposal to investigate if CB2 cannabinoid receptor agonist functional selectivity can be exploited to identify more specific and effective CB2 receptor agonists for the treatment of chronic pain. Functional selectivity (also known as biased agonism and ligand-directed trafficking) is an increasingly appreciated property of receptor signaling. When a functionally selective agonist binds to a receptor capable of activating multiple signaling pathways, only a subset of those pathways are activated, or the rank order potency of activating specific pathways varies among agonists. Most G protein-coupled receptors (GPCRs) engage multiple signaling pathways, offering many opportunities for functional selectivity. Functional selectivity has substantial therapeutic implications. Properly applied, it may allow activation of specific pathways that are beneficial for treating a specific condition, while avoiding activation of pathways that may contribute to unwanted side effects. Thus, functional selectivity adds another dimension beyond potency, subtype selectivity and intrinsic efficacy to GPCR agonists-a dimension that may be exploited for therapeutic benefit. In preliminary studies examining CB2 receptor signaling we identified striking functional selectivity in several classes of CB2 agonists. For example, members of the aminoalkylindole family of CB2 agonists activated several CB2 signaling pathways, but failed to inhibit voltage dependent calcium channels or internalize CB2 receptors. This degree of functional selectivity is important for both mechanistic and therapeutic reasons. Mechanistically, it offers us the possibility of identifying the signaling pathways underlying CB2-mediated analgesia in specific pain states. Therapeutically, it offers us the possibility of designing drugs that may be efficacious for pain based upon their functional selectivities, while lessening the possibility of undesired effects. Ths proposal will evaluate the therapeutic potential of functional selectivity of CB2 agonists through two specific aims. The first specific aim will complete the characterization of the signaling of currently available CB2 agonists, including CB2 agonists that have failed clinically, using a battery of biochemical and cell-based functional assays. The second specific aim will take the three compounds with the most striking functional selectivity in the in vitro assays and examine their efficacy in preclinical models of neuropathic (paclitaxel and spinal nerve ligation) and inflammatory (complete Freund's adjuvant) pain using CB1 receptor knockout mice. Efficacy of these functional selective CB2 agonists will be compared to a "balanced"-CB2 agonist (CP55,940) that activates all tested signaling pathways to a similar extent (see Table 1 in Research Strategy). Completion of these specific aims will give us a comprehensive understanding on how functional selectivity contributes to the therapeutic efficacy of CB2 ligands and also provide a rich pharmacological characterization of CB2 signaling that will be crucial for the future evaluation of CB2 agonists for other therapeutic indications.

描述（由申请人提供）：这是一项研究是否可以利用 CB2 大麻素受体激动剂功能选择性来鉴定用于治疗慢性疼痛的更特异和有效的 CB2 受体激动剂的提案。功能选择性（也称为偏向激动和配体定向运输）是受体信号传导日益受到重视的特性。当功能选择性激动剂与能够激活多个信号传导途径的受体结合时，只有这些途径的子集被激活，或者激活特定途径的等级顺序效力在激动剂之间变化。大多数 G 蛋白偶联受体 (GPCR) 参与多种信号传导途径，为功能选择性提供了许多机会。功能选择性具有重大的治疗意义。如果应用得当，它可以激活有利于治疗特定病症的特定途径，同时避免激活可能导致不良副作用的途径。因此，功能选择性为 GPCR 激动剂增加了除效力、亚型选择性和内在功效之外的另一个维度，这一维度可用于治疗益处。在检查 CB2 受体信号传导的初步研究中，我们发现几类 CB2 激动剂具有惊人的功能选择性。例如，CB2 激动剂的氨烷基吲哚家族成员激活了多个 CB2 信号通路，但未能抑制电压依赖性钙通道或内化 CB2 受体。这种程度的功能选择性对于机制和治疗原因都很重要。从机制上讲，它为我们提供了识别特定疼痛状态下 CB2 介导的镇痛作用的信号通路的可能性。在治疗上，它为我们提供了根据其功能选择性设计对疼痛有效的药物的可能性，同时减少了不良反应的可能性。该提案将通过两个具体目标评估 CB2 激动剂功能选择性的治疗潜力。第一个具体目标将使用一系列生化和基于细胞的功能测定来完成目前可用的 CB2 激动剂（包括临床上失败的 CB2 激动剂）信号传导的表征。第二个具体目标是在体外试验中采用三种具有最显着功能选择性的化合物，并使用 CB1 受体敲除小鼠检查它们在神经性疼痛（紫杉醇和脊神经结扎）和炎症性疼痛（完全弗氏佐剂）疼痛的临床前模型中的功效。这些功能性选择性 CB2 激动剂的功效将与“平衡”-CB2 激动剂 (CP55,940) 进行比较，后者以相似的程度激活所有测试的信号通路（参见研究策略中的表 1）。完成这些具体目标将使我们全面了解功能选择性如何促进 CB2 配体的治疗功效，并提供丰富的 CB2 信号传导药理学特征，这对于未来评估 CB2 激动剂用于其他治疗适应症的作用至关重要。