Development of Peripherally-acting Cannabinoid 1 Receptor Ligands

描述(申请人提供)：合成和自然产生的大麻素是关于其治疗作用的强烈社会、法律和医学争议的焦点，但研究表明，大麻素可以减少与人类和动物的神经病理性持续性疼痛有关的痛觉过敏和超敏。此外，与阿片类药物不同，大麻类药物在反复治疗后在缓解神经病理性疼痛症状方面有效，而阿片类药物的效果有限。然而，现有的以大麻素为基础的止痛药的有效性受到其精神副作用的限制。大麻素受体的两个亚型CB1R和CB2R的分布可以确定大麻素的靶标。这两个受体都是G蛋白偶联受体超家族的成员，CB1R在海马、皮质、小脑和基底节高水平表达，而CB2R主要在中枢神经系统(CNS)以外的免疫活性细胞中表达。CB1Rs也在中枢神经系统外被发现，特别是在初级感觉神经元中，这是过度兴奋的常见来源，被认为是许多神经疾病疼痛症状的罪魁祸首。在这个探索性和发展性研究项目中，我们寻求(目标1)通过设计由于带电化合物而无法跨越血脑屏障的类似物来开发CB1Rs的外周作用配体。在合成后，这些化合物将与它们的亲本脑渗透性CB1R配体进行比较，以了解它们激活CB1R的能力，方法是采用成熟的体外CB1R筛选试验(AIM 2)。有希望的配体将在另一项体外试验中筛选血脑屏障通透性，以估计化合物可能通过中枢神经系统的程度。随后将(目标3)研究外周作用配体在减轻周围神经病大鼠模型疼痛症状方面的有效性。最有希望的化合物还将在改进的四分体试验中检查潜在的中枢神经系统副作用。从这个试点项目中获得的数据有望被证明对开发新的止痛药用于治疗神经病理性慢性疼痛是有用的。我们的策略还可能有助于理解大麻素受体的药理学，并引入一套新的工具，帮助研究外周大麻素受体的生理和病理生理学意义。与公共卫生相关的神经病理性疼痛极难治疗，部分原因是现有药物具有很高的中枢神经系统副作用负担。在这里，我们建议设计和测试大麻素受体配体的类似物，这些配体由于其带电化合物而无法通过血脑屏障。因此，我们希望这些药物表现出最小的精神副作用的止痛特性。

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.