Development of CB2 Agonists for Treatment of Pain

描述(由申请者提供)：据估计，大约45%的美国人口寻求治疗疼痛的医疗帮助。慢性疼痛可能是由各种疾病引起的，如糖尿病、类风湿性关节炎、下腰痛、癌症、多发性硬化症和艾滋病毒。可用于治疗慢性疼痛的治疗选择是不够的。因此，需要新的药物策略来治疗这种慢性疾病。大麻素CB2受体是治疗炎症和疼痛的一个有前途的药物靶点。我们的目标是开发一种高效的CB2受体激动剂，因为这种激动剂可能会减轻疼痛，副作用比也激活CB1受体的非选择性大麻素少。这项建议的具体目的是通过我们的新型THC/ANANDIAME杂化模板的结构优化，开发一种对CB1具有良好效力、有效性和选择性的CB2激动剂。我们计划根据我们的合成孔径雷达结果开发一种药效团，然后可以用来设计更有效的类似物。为了区分激动剂和拮抗剂的活性，有效结合CB2受体的类似物将被评估它们刺激[35S]GTP3S结合的能力。具有高受体亲和力并能有效刺激[35S]GTP3S结合的化合物将在小鼠四分体模型中进行活性测试。在小鼠四分体模型中显示活性很小的类似物将在脂多糖模型中进行评估，然后是福尔马林模型和CCI模型。这项建议的长期目标是开发一种选择性和有效的CB2激动剂，具有抑制疼痛的潜力，然后可以作为开发治疗慢性疼痛的药物的先导。公共卫生相关性：CB2受体是治疗炎症和慢性疼痛的药物设计的一个有吸引力的靶点。这项建议的长期目标是开发一种治疗慢性疼痛状况的药物，而不会产生不良的中枢神经系统副作用。

DESCRIPTION (provided by applicant): It has been estimated that about 45% of the U. S. population seeks medical help for pain. Chronic pain can result from various disease conditions such as diabetes, rheumatoid arthritis, lower back pain, cancer, MS and HIV. The available therapeutic options for the treatment of chronic pain are inadequate. Therefore novel drug strategies are needed to treat this chronic condition. A promising drug target for treatment of inflammation and pain is the cannabinoid CB2 receptor. Our goal is to develop a high efficacy CB2 receptor agonist, because such agonists are likely to reduce pain, with fewer side effects than nonselective cannabinoids that also activate CB1 receptors. The specific aim of this proposal is to develop a CB2 agonist with good potency, efficacy and selectivity with respect to CB1 by structural optimization of our novel THC/anandamide hybrid template. We plan on developing a pharmacophore based on our SAR results which could then be used to design more active analogs. In order to distinguish between agonist and antagonist activity, analogs which bind effectively to the CB2 receptor will be evaluated for their ability to stimulate [35S]GTP3S binding. Compounds with high receptor affinity and which are active in stimulating [35S]GTP3S binding will then be tested for activity in the mouse tetrad model. Analogs that show little activity in the mouse tetrad model will then be evaluated in the LPS model followed by the formalin model and CCI model. The long term goal of this proposal is to develop a selective and potent CB2 agonist with pain suppression potential which could then be used as a lead in the development of a drug for the treatment of chronic pain. PUBLIC HEALTH RELEVANCE: CB2 receptor is an attractive target for the design of medication to treat inflammation and chronic pain. The long-term goal of this proposal is to develop a medication for the treatment of chronic pain conditions without undesirable CNS side effects.