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）：合成和自然发生的大麻素是有关其治疗效用的强烈社会，法律和医学争议的重点，但研究表明，大麻素降低了与人类和动物神经病变持续性疼痛相关的痛苦和异常性疾病。此外，与阿片类药物不同，大麻素可以有效缓解反复治疗后的神经性疼痛症状，而阿片类药物的有效性仅有限。但是，现有的基于大麻素的镇痛药的有用性受其精神副作用的概况的限制。大麻素的靶标可以通过大麻素受体CB1R和CB2R的两个克隆亚型的分布来定义。两者都是G蛋白偶联受体的超家族的成员，在海马，皮层，小脑和基底神经节中，CB1RI在高水平中表达，而CB2R则主要在中枢神经系统（CNS）以外的免疫能力细胞中表达。 CB1R在中枢神经系统之外还发现了CB1R，特别是在原发性感觉神经元中，这是导致许多神经病疼痛症状的过度兴奋性的常见来源。在这个探索性和发展研究项目中，我们试图（AIM 1）通过设计无法通过充电化合物来设计无法越过血脑屏障的类似物来在CB1RS上开发外围作用的配体。合成后，将将这些化合物与其母脑可渗透的CB1R配体进行比较，以使用良好的体外CB1R筛选分析来激活CB1RS（AIM 2）。在另一种体外测定中，将筛选有前途的配体以获取血脑屏障的渗透性，以估计化合物CNS渗透的可能程度。这些将在（目标3）研究外周作用配体在减少周围神经病大鼠模型中的疼痛症状方面的有效性。最有希望的化合物还将在修饰的四型测定法中检查潜在的CNS副作用。从该试验项目中获得的数据有望被证明可用于开发新的镇痛药，以治疗神经性起源的慢性疼痛。我们的策略还可能有助于理解大麻素受体药理学，并引入一套新型的工具，这些工具可以帮助研究外周外大麻素受体的生理和病理生理学重要性。公共卫生相关性神经性疼痛极为难以治疗，部分原因是可用的药物承受着高负担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，这些配体因其充电化合物而无法越过血脑屏障。结果，我们期望这些药物具有最小的精神副作用的镇痛性能。