Exploiting CB2 Functional Selectivity for Therapeutic Benefit

利用 CB2 功能选择性获得治疗效果

基本信息

批准号：
8742285
负责人：
Kenneth Mackie
金额：
$ 23.05万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8742285
关键词：
Active Sites Acute Adenylate Cyclase Adverse effects Agonist Behavioral Behavioral Assay Biological Assay CNR1 gene CNR2 gene Calcium Channel Cell Line Chemicals Chronic Clinical Cocaine Data Analyses Development Employee Strikes Endocannabinoids Exhibits Freund&apos s Adjuvant Funding Future Huntington Disease Hyperalgesia In Vitro Inflammation Inflammatory Knowledge Ligands Locomotion Maps Mediating Methodology Mitogen-Activated Protein Kinases Modeling Molecular Conformation Monitor Mus Nerve Degeneration Neuropathy Nociception Outcome Paclitaxel Pain Pathologic Processes Pattern Pharmaceutical Chemistry Pharmaceutical Preparations Positioning Attribute Potassium Channel Pre-Clinical Model Process Receptor Activation Research Rewards Signal Pathway Signal Transduction Synaptic Transmission Testing Therapeutic Transgenic Mice Translating Translations Treatment Efficacy Work abstracting allodynia base chemotherapy induced neuropathy chronic pain design drug development in vitro Assay in vivo inflammatory pain interest migration mouse model neuroinflammation novel painful neuropathy pre-clinical preclinical study preference prevent receptor internalization research study therapeutic target

项目摘要

RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT CB2 cannabinoid receptor agonists show intriguing therapeutic promise in diverse preclinical models. However, the lack of detailed information about the signal transduction mechanisms underlying the observed in vivo efficacies has thwarted translational efforts aimed at developing CB2-based therapeutics. We have recently described striking functional selectivity (whereby different agonists activate distinct networks of signaling pathways) among different CB2 agonists. We hypothesize that the inability to move CB2 agonists forward from preclinical development to novel therapies is in part due to an insufficient appreciation of the functional selectivity of this class of drugs. We contend that understanding of the mechanism of CB2 agonist functional selectivity is a prerequisite for rationally designing CB2 agonists exhibiting functional selectivity for specific classical CB2 agonist signaling pathways. We will test the hypothesis that selective activation of a restricted set of signaling pathways will produce unique therapeutic benefits by evaluating the effects of novel, functionally selective CB2 agonists in four different preclinical models. This project works iteratively with Core B, and Projects 1 & 2 to systematically evaluate functional selectivity of the novel CB2 agonists synthesized in Project 1 (in vitro assays) and determine if CB2 agonist functional selectivity can be exploited to develop more efficacious CB2 agonists for the treatment of chronic pain, inflammation, and reward (in vivo assays). We will test our central hypothesis and accomplish these objectives by completing two specific aims: 1. To characterize the in vitro functional selectivity of rationally designed CB2 agonists from distinct chemical classes. The compounds showing the most distinct profiles of functional selectivity will then be advanced to the second specific aim. 2. To identify the optimal functional selectivity profile of CB2 agonists for suppressing neuropathic pain, inflammation, and reward in vivo. The most promising compounds identified in Aim 1 will be evaluated in Aim 2 for efficacy with acute and chronic (as appropriate) treatment. Completion of the first aim will map CB2 agonist chemotypes associated to specific patterns of functional selectivity. The second aim will identify signaling networks required to suppress neuropathic pain, inflammation, or reward in our preclinical models, which may or may not involve overlapping functional selectivity profiles. (This approach will also identify the signaling pathways that are not necessary (i.e. dispensable) for a particular behavioral outcome, which is important information to obtain and will be a helpful guide for future medicinal chemistry efforts.) Together, the knowledge gained from these aims will allow us and others to develop novel CB2 ligands with focused pharmacological efficacy and possibly reduced side-effects for treating indications where CB2 agonists are likely to prove beneficial.

研究与相关 - 其他项目信息 - 项目摘要/摘要 CB2大麻素受体激动剂在各种临床前模型中表现出有趣的治疗前景。但是，缺乏有关观察到的信号转导机制的详细信息体内效率挫败了旨在开发基于CB2的治疗剂的转化工作。我们有最近描述了惊人的功能选择性（不同的激动剂激活了不同的网络信号通路）在不同的CB2激动剂中。我们假设无法移动CB2激动剂从临床前开发到新疗法的前进部分是由于对这类药物的功能选择性。我们认为对CB2激动剂机制的理解功能选择性是合理设计CB2激动剂的先决条件，表现出功能选择性特定的经典CB2激动剂信号通路。我们将检验以下假设：受限制的信号通路集将通过评估新颖的影响，从而产生独特的治疗益处在四个不同的临床前模型中，功能性选择性CB2激动剂。该项目与核心迭代合作 B，以及系统1和2的项目，以系统地评估新型CB2激动剂合成的功能选择性项目1（体外测定），并确定是否可以利用CB2激动剂功能选择性来发展更多有效的CB2激动剂治疗慢性疼痛，炎症和奖励（体内测定）。我们将通过完成两个具体目标来检验我们的中心假设并实现这些目标： 1。表征来自不同不同的cb2激动剂的体外功能选择性化学类。然后，显示最不同的功能选择性曲线的化合物将提高到第二个特定目标。 2。确定CB2激动剂的最佳功能选择性特征以抑制神经性疼痛，炎症和体内奖励。 AIM 1中确定的最有希望的化合物将在AIM 2中评估，以使急性和慢性（适当）治疗。第一个目标的完成将绘制与功能选择性的特定模式。第二个目标将确定抑制所需的信号网络在我们的临床前模型中，神经性疼痛，炎症或奖励可能涉及或不涉及重叠功能选择性概况。（这种方法还将确定不需要的信号通路（即可分配）对于特定的行为结果，这是要获得的重要信息，将是一个有助于未来药物化学工作的指南。）共同，从这些目标中获得的知识将允许我们和其他人开发具有重点药理功效的新型CB2配体，并可能降低治疗CB2激动剂可能有益的副作用。