Development of CB2 Agonists for Treatment of Pain

开发用于治疗疼痛的 CB2 激动剂

基本信息

批准号：
7641367
负责人：
Anuradha Mahadevan
金额：
$ 26.44万
依托单位：
ORGANIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7641367
关键词：
2-arachidonylglycerol Adverse effects Affinity Agonist Amides Animal Model Binding Biological Process CNR1 gene CNR2 gene Cannabinoids Chronic Clinical Treatment Clinical Trials Development Diabetes Mellitus Disease Drug Delivery Systems Ethanolamines Expenditure Formalin Goals HIV Hybrids Hydroxyl Radical Inflammation Injury Lead Ligands Low Back Pain Malignant Neoplasms Medical Metabolic Modeling Modification Mus National Institute of Drug Abuse Nervous system structure Neuraxis Neuropathy Outcome Oxadiazoles Oxazoles Pain Peripheral Persistent pain Pharmaceutical Preparations Population Positioning Attribute Postherpetic neuralgia Quality of life Receptor Activation Recommendation Research Rheumatoid Arthritis Series Side Structure-Activity Relationship System Testing Tetrahydrocannabinol Therapeutic Tissues Work Workplace addiction analog anandamide base cannabinoid receptor chronic pain design endogenous cannabinoid system experience functional group hydroxyl group immune function inflammatory neuropathic pain inflammatory pain medical appointment novel pharmacophore pi bond productivity loss public health relevance receptor response

项目摘要

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.

描述（由申请人提供）：据估计，大约 45% 的美国人因疼痛而寻求医疗帮助。慢性疼痛可能由多种疾病引起，例如糖尿病、类风湿性关节炎、腰痛、癌症、多发性硬化症和艾滋病毒。治疗慢性疼痛的可用治疗方案不足。因此，需要新的药物策略来治疗这种慢性病。治疗炎症和疼痛的一个有前景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，因为此类激动剂可能会减轻疼痛，并且比同时激活 CB1 受体的非选择性大麻素副作用更少。该提案的具体目标是通过我们新型 THC/anandamide 混合模板的结构优化，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 结果开发一种药效团，然后将其用于设计更具活性的类似物。为了区分激动剂和拮抗剂活性，将评估与CB2受体有效结合的类似物刺激[35S]GTP3S结合的能力。然后将测试具有高受体亲和力并且具有刺激[35S]GTP3S结合活性的化合物在小鼠四分体模型中的活性。在小鼠四分体模型中表现出很少活性的类似物将在 LPS 模型中进行评估，然后在福尔马林模型和 CCI 模型中进行评估。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、强效 CB2 激动剂，然后可用作开发治疗慢性疼痛的药物的先导药物。公共卫生相关性：CB2 受体是治疗炎症和慢性疼痛药物设计的一个有吸引力的目标。该提案的长期目标是开发一种治疗慢性疼痛的药物，且不会产生不良的中枢神经系统副作用。