Development of Peripherally-acting Cannabinoid 1 Receptor Ligands

外周作用大麻素 1 受体配体的开发

• 批准号: 7588613
• 负责人: IGOR SPIGELMAN
• 金额: $ 25.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588613
• 关键词: 2-arachidonylglycerol; Accounting; Acute; Adverse effects; Affect; Afferent Neurons; Agonist; Ammonium; Analgesics; Animals; Basal Ganglia; Biological Assay; Blood - brain barrier anatomy; Brain; Cannabinoids; Catalepsy; Cells; Cerebellum; Charge; Chung model; Cognitive; Data; Development; Effectiveness; Endocannabinoids; Engineering; Exhibits; G-Protein-Coupled Receptors; Head; Hippocampus (Brain); Human; Hyperalgesia; Immunocompetent; In Vitro; Indenes; Indoles; Laboratories; Learning; Legal; Ligands; Ligation; Lipids; Measures; Mechanics; Mediating; Medical; Memory; Modeling; Modification; Neuraxis; Neuropathy; Opioid; Opioid Analgesics; Pain; Parents; Penetration; Peripheral; Peripheral Nervous System Diseases; Peripheral nerve injury; Permeability; Persistent pain; Pharmaceutical Preparations; Pharmacology; Physiological; Pilot Projects; Plants; Population; Property; Public Health; Radioactive; Rattus; Receptor Activation; Research; Research Project Grants; Screening procedure; Site; Source; Spinal; Spinal nerve structure; Structure; Symptoms; System; Tail; Task Performances; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thermal Hyperalgesias; Tissues; allodynia; analog; anandamide; base; cannabinoid receptor; chronic neuropathic pain; chronic pain; design; dorsal horn; in vitro Assay; member; midbrain central gray substance; natural hypothermia; novel; painful neuropathy; public health relevance; receptor; social; tool; transmission process

DESCRIPTION (provided by applicant): Synthetic and naturally occurring cannabinoids are a focus of strong social, legal and medical controversy concerning their therapeutic utility, yet studies show that cannabinoids reduce the hyperalgesia and allodynia associated with persistent pain of neuropathic origin in humans and animals. Moreover, cannabinoids are effective in alleviating neuropathic pain symptoms after repeated treatment, unlike opioids, which have only limited effectiveness. However, the usefulness of existing cannabinoid-based analgesics is limited by their profile of psychotropic side-effects. The targets of cannabinoids may be defined by the distribution of two cloned subtypes of cannabinoid receptors, CB1R and CB2R. Both are members of the superfamily of G protein- coupled receptors of which CB1Ris expressed at high levels in the hippocampus, cortex, cerebellum and basal ganglia, whereas CB2R is primarily expressed in immunocompetent cells outside the central nervous system (CNS). CB1Rs are also found outside the CNS, especially in primary sensory neurons which are common sources of hyperexcitability thought responsible for the painful symptoms of many neuropathies. In this Exploratory and Developmental Research Project we seek to (Aim 1) develop peripherally-acting ligands at CB1Rs by designing analogs that are unable to cross the blood-brain barrier by virtue of their being charged compounds. Following their synthesis, these compounds will be compared with their parent brain-permeable CB1R ligands for their ability to activate CB1Rs using well established in vitro CB1R screening assays (Aim 2). Promising ligands will be screened for blood-brain barrier permeability in another in vitro assay to estimate the likely extent of the compounds' CNS penetration. These will be followed by (Aim 3) studying the effectiveness of peripherally-acting ligands in reducing the pain symptoms in a rat model of peripheral neuropathy. The most promising compounds will also be examined for potential CNS side effects in a modified tetrad assay. The data obtained from this pilot project are expected to prove useful to the development of new analgesics for the treatment of chronic pain of neuropathic origin. Our strategy may also contribute to the understanding of cannabinoid receptor pharmacology and to introduce a novel set of tools that can help study the physiological and pathophysiological importance of peripheral cannabinoid receptors. PUBLIC HEALTH RELEVANCE Neuropathic pain is extremely difficult to treat, in part because available drugs carry a high burden of central nervous system side-effects. Here we propose to design and test analogs of cannabinoid receptor ligands that are unable to cross the blood-brain barrier by virtue of their being charged compounds. As a result, we expect these drugs to exhibit analgesic properties with minimal psychotropic side-effects.

描述（由申请人提供）：合成和天然存在的大麻素是其治疗效用的强烈社会、法律和医学争议的焦点，但研究表明，大麻素可减轻与人类和动物神经源性持续性疼痛相关的痛觉过敏和异常性疼痛。此外，大麻素在重复治疗后可有效缓解神经性疼痛症状，而阿片类药物的效果有限。然而，现有的基于大麻素的镇痛药的用途受到其精神副作用的限制。大麻素的靶标可以通过大麻素受体的两种克隆亚型 CB1R 和 CB2R 的分布来定义。两者都是 G 蛋白偶联受体超家族的成员，其中 CB1Ri 在海马、皮质、小脑和基底神经节中高水平表达，而 CB2R 主要在中枢神经系统 (CNS) 以外的免疫活性细胞中表达。 CB1R 也存在于中枢神经系统之外，特别是在初级感觉神经元中，它们是过度兴奋的常见来源，被认为是许多神经病疼痛症状的原因。在这个探索性和发展研究项目中，我们寻求（目标 1）通过设计由于带电化合物而无法穿过血脑屏障的类似物来开发 CB1R 的外周作用配体。合成后，将使用成熟的体外 CB1R 筛选测定法（目标 2）将这些化合物与其母体脑渗透性 CB1R 配体比较其激活 CB1R 的能力。将在另一项体外测定中筛选有前景的配体的血脑屏障渗透性，以估计化合物渗透中枢神经系统的可能程度。接下来（目标 3）研究外周作用配体在减轻周围神经病大鼠模型中疼痛症状方面的有效性。最有前途的化合物还将在改进的四分体测定中检查潜在的中枢神经系统副作用。从该试点项目获得的数据预计将有助于开发用于治疗神经源性慢性疼痛的新型镇痛药。我们的策略还可能有助于理解大麻素受体药理学，并引入一套新的工具，可以帮助研究外周大麻素受体的生理和病理生理学重要性。公共健康相关性 神经性疼痛极难治疗，部分原因是现有药物会带来沉重的中枢神经系统副作用。在这里，我们建议设计和测试大麻素受体配体的类似物，它们由于带电化合物而无法穿过血脑屏障。因此，我们期望这些药物具有镇痛特性，同时精神副作用最小。