Development of CB2 Agonists for Treatment of Pain

描述（由申请人提供）：据估计，约有45%的美国人因疼痛寻求医疗帮助。慢性疼痛可由各种疾病引起，如糖尿病、风湿性关节炎、腰痛、癌症、多发性硬化症和艾滋病毒。治疗慢性疼痛的现有治疗选择是不足的。因此，需要新的药物策略来治疗这种慢性疾病。治疗炎症和疼痛的一个有希望的药物靶点是大麻素CB2受体。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减轻疼痛，副作用比激活CB1受体的非选择性大麻素更少。本提案的具体目标是通过对我们的新型THC/anandamide杂交模板进行结构优化，开发一种相对于CB1具有良好效力，功效和选择性的CB2激动剂。我们计划根据我们的SAR结果开发一个药效团，然后可以用来设计更有活性的类似物。为了区分激动剂和拮抗剂的活性，将评估与CB2受体有效结合的类似物刺激[35S]GTP3S结合的能力。具有高受体亲和力且刺激[35S]GTP3S结合活性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很少活性的类似物随后将在LPS模型中进行评估，然后是福尔马林模型和CCI模型。这项提议的长期目标是开发一种具有疼痛抑制潜力的选择性和有效的CB2激动剂，然后可以用作开发治疗慢性疼痛的药物的先导。公共卫生相关性：CB2受体是设计治疗炎症和慢性疼痛的药物的一个有吸引力的靶点。这项提议的长期目标是开发一种治疗慢性疼痛的药物，而不会对中枢神经系统产生不良副作用。

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.