Project 3 - In vivo pharmacology of cannabinoid receptor probes

项目3-大麻素受体探针的体内药理学

• 批准号: 10333996
• 负责人: Andrea Grace Hohmann
• 金额: $ 21.23万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333996
• 关键词: 2-arachidonylglycerol; Active Sites; Affinity; Agonist; Anxiety; Binding; Binding Sites; Biological; CNR1 gene; CNR2 gene; Cannabinoids; Cessation of life; Chemicals; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical Trials; Complex; Development; Dose; Endocannabinoids; Exhibits; Failure; Future; G-Protein-Coupled Receptors; Human; In Vitro; Intoxication; Knockout Mice; Knowledge; Ligands; Medicine; Modeling; Mus; Neuropathy; Nociception; Pain; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Property; Proteins; Receptor Signaling; Research; Signal Pathway; Signal Transduction; Site; Stress; System; Testing; Therapeutic; Translating; Translations; Treatment Efficacy; anandamide; animal pain; antagonist; base; cannabimimetics; cannabinoid receptor; clinical translation; cost; drug development; drug discovery; endocannabinoid signaling; endogenous cannabinoid system; improved; in vivo; in vivo evaluation; insight; knowledge base; mu opioid receptors; negative affect; novel; pain model; positive allosteric modulator; pre-clinical research; preclinical study; preservation; side effect; therapeutic target

Project Summary The therapeutic potential of the endocannabinoid system has yet to translate into safe and effective medicines. The translation gap, or “valley of death” separates promising preclinical research from identification of a newly approved drug. Functional selectivity (or biased agonism) is a recently appreciated property of CB1 and CB2 receptor signalling. Challenges for clinical translation include the question of what signalling pathway best predicts therapeutic efficacy. It is, therefore, necessary to establish that candidate ligands engage the specific signalling pathways necessary for therapeutic benefit, while, ideally, circumventing those pathways responsible for unwanted side effects. Both biased agonism and allosteric modulation represent alternative strategies to harness the therapeutic potential of the endocannabinoid signalling system without the unwanted effects of direct acting CB1 agonists. The signalling pathways necessary and dispensable for CB1 and CB2 therapeutic efficacy remain poorly understood. Bridging this gap in knowledge is critical if we are to avoid costly failures in clinical translation. Project 3 will use novel CB1 and CB2 probes that are developed in Project 1 and characterized in vitro in Project 2 to elucidate how CB1 biased agonism, probe specific CB1 positive allosteric modulation and CB2 selective agonism impact in vivo pharmacology. Aim 1 will define the in vivo pharmacology of functionally selective CB1 probes. We will profile functionally selective CB1 agonists as well as tight binding (slow Koff) and probe-specific CB1 PAMs (that exhibit high potency in our preliminary in vivo studies) for cardinal signs of CB1 activation, ability to suppress neuropathic nociception as well as propensity to induce tolerance and physical dependence. Aim 2 will define the in vivo pharmacology of CB2 agonists with improved selectivity for CB2 over CB1. We will ascertain whether in vivo pharmacological profiles and selectivity can be improved by incorporating high affinity CB2 agonism with a lack of CB1 agonism. We will also determine whether in vivo pharmacological profiles can be enhanced by incorporating CB1 antagonism (neutral, inverse agonism, partial agonism) with high affinity CB2 agonism. This Aim will compare a spectrum of ligands exhibiting these properties for cannabimimetic effects, anti-allodynic efficacy and tolerance, as well as capacity to induce physical dependence and negative affective states. This project will validate improved CB1 and CB2 probes, not to develop a medication. Elucidation of signalling pathways necessary and dispensable for in vivo efficacy and unwanted side effects will improve cannabinoid-based therapeutics and break down barriers to successful clinical translation.

项目摘要 内源性大麻素系统的理论潜力尚未转化为安全有效 药物。翻译差距或“死亡谷”将有希望的临床前研究与 鉴定新认可的药物。功能选择性（或偏见激动剂）是最近的欣赏 CB1和CB2受体信号的特性。临床翻译的挑战包括什么问题 信号通路最能预测治疗效率。因此，有必要建立该候选人 配体参与热益处所需的特定信号通路，理想情况下， 规避那些负责不需要副作用的途径。偏见激动和变构 调制代表了利用内源性大麻素的治疗潜力的替代策略 信号系统没有直接作用CB1激动剂的不良影响。信号通路 CB1和CB2治疗效率的必要且易于使用。桥接这个 如果我们要避免临床翻译中昂贵的失败，知识的差距至关重要。项目3将使用小说CB1 项目1中出现的CB2问题并在项目2中在体外进行了表征，以阐明CB1如何 偏置激动剂，探针特异性CB1阳性变构调制和CB2选择性激动剂影响体内 药理。 AIM 1将定义功能性选择性CB1探针的体内药理学。我们将概括 在功能上选择性CB1激动剂以及紧密的结合（慢速KOFF）和探针特异性的CB1 PAM（即 在我们的初步体内研究中表现出很高的效力）CB1激活的基本迹象，抑制能力 神经性肿瘤以及诱导耐受性和身体依赖性的倾向。 AIM 2将定义 CB2激动剂的体内药理学对CB2的选择性提高了CB1。我们将确定 通过合并高亲和力CB2是否可以提高体内药理学特征和选择性 动力学缺乏CB1激动剂。我们还将确定体内药理学特征是否可以 通过将CB1拮抗作用（中性，反激动剂，部分激动剂）和高亲和力CB2融合来增强 激动剂。该目标将比较一系列具有这些特性的配体，以实现大麻效应， 反合金效率和耐受性，以及诱导身体依赖性和负面的能力 情感状态。该项目将验证改善的CB1和CB2问题，而不是开发药物。 阐明必要的信号通路，可用于体内效率和不必要的副作用 将改善基于大麻素的治疗，并打破成功临床翻译的障碍。