Development of CB2 Agonists for Treatment of Pain

描述（由申请人提供）：据估计，约45%的美国。S.人们因疼痛而寻求医疗帮助。慢性疼痛可以由各种疾病引起，如糖尿病、类风湿性关节炎、腰痛、癌症、MS和HIV。治疗慢性疼痛的现有治疗选择不足。因此，需要新的药物策略来治疗这种慢性疾病。用于治疗炎症和疼痛的有希望的药物靶标是大麻素CB 2受体。我们的目标是开发一种高效的CB 2受体激动剂，因为这种激动剂可能会减少疼痛，副作用比也激活CB 1受体的非选择性大麻素少。本提案的具体目的是通过我们的新型THC/大麻素杂合模板的结构优化，开发相对于CB 1具有良好效力、功效和选择性的CB 2激动剂。我们计划根据我们的SAR结果开发药效团，然后可以用于设计更活跃的类似物。为了区分激动剂和拮抗剂活性，将评价有效结合CB 2受体的类似物刺激[35 S] GTP 3S结合的能力。然后在小鼠四分体模型中测试具有高受体亲和力且在刺激[35 S] GTP 3S结合中具有活性的化合物的活性。在小鼠四分体模型中显示出很小活性的类似物随后将在LPS模型中进行评价，随后在福尔马林模型和CCI模型中进行评价。该提案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CB 2激动剂，然后可以用作开发治疗慢性疼痛的药物的领导者。公共卫生相关性：CB 2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。该提案的长期目标是开发一种用于治疗慢性疼痛状况而没有不良CNS副作用的药物。

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.