Development of Peripherally-acting Cannabinoid 1 Receptor Ligands

描述（由申请人提供）：合成的和天然存在的大麻素是关于其治疗效用的强烈的社会、法律的和医学争议的焦点，然而研究表明大麻素减少与人类和动物中的神经性起源的持续性疼痛相关的痛觉过敏和异常性疼痛。此外，大麻素在反复治疗后可有效缓解神经性疼痛症状，而阿片类药物的有效性有限。然而，现有的基于大麻素的镇痛剂的有用性受到其精神病副作用的限制。大麻素的靶点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CB1R在海马、皮质、小脑和基底神经节中以高水平表达，而CB2R主要在中枢神经系统（CNS）外的免疫活性细胞中表达。CB1R也存在于CNS外，特别是在初级感觉神经元中，初级感觉神经元是过度兴奋的常见来源，被认为是许多神经病的疼痛症状的原因。在这个探索性和发展性研究项目中，我们寻求（目标1）通过设计类似物来开发CB1R的外周作用配体，这些类似物由于其带电化合物而无法穿过血脑屏障。合成后，将使用完善的体外CB1R筛选测定法（Aim 2）比较这些化合物与其母体脑渗透性CB1R配体激活CB1R的能力。将在另一个体外试验中筛选有希望的配体的血脑屏障渗透性，以估计化合物的CNS渗透的可能程度。这些之后将是（目的3）研究外周作用配体在减轻外周神经病大鼠模型中的疼痛症状中的有效性。最有希望的化合物也将在改良的四分体测定中检查潜在的CNS副作用。从这个试点项目获得的数据预计将证明有用的新的镇痛药的发展，用于治疗慢性疼痛的神经源性。我们的策略也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重要性。公共卫生相关性神经性疼痛极难治疗，部分原因是现有药物具有中枢神经系统副作用的高负担。在这里，我们建议设计和测试大麻素受体配体的类似物，这些配体由于它们是带电的化合物而不能穿过血脑屏障。因此，我们期望这些药物表现出镇痛特性，同时具有最小的精神病副作用。

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.