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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要内源性大麻素系统的治疗潜力尚未转化为安全有效的翻译差距或“死亡之谷”将有前途的临床前研究与药物分开。功能选择性（或偏向激动）的鉴定最近受到重视。 CB1 和 CB2 受体信号传导的特性对临床转化的挑战包括什么问题。因此，有必要确定该候选信号通路。配体参与特定的信号传导途径以获得治疗益处，而理想情况下，规避那些导致不良副作用的途径，包括偏向激动和变构。调制代表了利用内源性大麻素治疗潜力的替代策略信号系统，没有直接作用的 CB1 激动剂的不良影响。 CB1 和 CB2 治疗功效的必要性和可有可无性仍然知之甚少。如果我们要避免临床转化中代价高昂的失败，知识差距就至关重要。项目 3 将使用新型 CB1。以及项目 1 中开发的 CB2 探针，并在项目 2 中进行体外表征，以阐明 CB1 如何偏向激动、探针特异性 CB1 正向变构调节和 CB2 选择性激动在体内的影响目标 1 将定义功能选择性 CB1 探针的体内药理学。功能选择性 CB1 激动剂以及紧密结合（慢 Koff）和探针特异性 CB1 PAM（即在我们的初步体内研究中表现出高效能）对于 CB1 激活的主要迹象、抑制能力目标 2 将定义神经性伤害感受以及诱发耐受性和身体依赖性的倾向。我们将确定 CB2 激动剂对 CB2 的选择性优于 CB1 的体内药理学。是否可以通过掺入高亲和力 CB2 来改善体内药理学特征和选择性我们还将确定是否可以确定体内药理学特征。通过将 CB1 拮抗作用（中性、反向激动、部分激动）与高亲和力 CB2 相结合来增强该目标将比较具有这些特性的配体的拟大麻作用，抗异常性疼痛的功效和耐受性，以及诱导身体依赖性和负性的能力该项目将验证改进的 CB1 和 CB2 探针，而不是开发药物。阐明信号传导的必要途径，并且对于体内功效和不良副作用而言是可有可无的将改善基于大麻素的疗法并打破成功临床转化的障碍。