Cannabinoid Receptor Agonists for Treatment of Chronic Pain

描述(申请人提供)：慢性疼痛可由各种疾病引起，约45%的美国人寻求治疗疼痛的医疗帮助。神经病理性疼痛是一种很难治疗的慢性疼痛，大多数患者得不到足够的缓解。大麻素CB2受体是治疗炎症和疼痛的一个有前途的治疗药物靶点。在这项提议的第一阶段，我们的重点将放在我们的先导模板的结构优化上，以开发一种具有止痛潜力且没有中枢神经系统副作用的高效CB2选择性激动剂。已建立的体内和体外药理试验将被用于鉴定以下化合物：1)对CB2比CB1受体具有高度的选择性；2)具有与CB2受体结合和激活的高效力和高效力；3)在逆转超敏反应(即对正常非伤害性刺激的伤害性行为)方面具有高效率；以及4)在整个动物中缺乏典型的CB1受体激活的拟大麻副作用。这项建议的长期目标是开发一种既安全又有效的治疗慢性疼痛的新药。

DESCRIPTION (provided by applicant): Chronic pain can result from various disease conditions and about 45% of the U. S. population seeks medical help for treatment of pain. Neuropathic pain is a type of chronic pain which is very difficult to treat, and most patients do not get adequate relief. A promising therapeutic drug target for the treatment of inflammation and pain is the cannabinoid CB2 receptor. In Phase I of this proposal our focus will be on the structural optimization of our lead template to develop a high efficacy CB2 selective agonist with pain suppression potential and with no CNS side effects. Established in vivo and in vitro pharmacological assays will be used to identify compounds that: 1) are highly selective for CB2 over CB1 receptors; 2) possess high efficacy and high potency in binding and activating the CB2 receptor; 3) possess high efficacy in reversing allodynia (i.e., nociceptive behavior in response to normally non-noxious stimuli); and 4) lack cannabimimetic side effects in whole animals that are typically indicative of CB1 receptor activation. The long-term objective of this proposal is to develop a novel drug for treatment of chronic pain which is both safe and effective.