Assay development for characterization of Adrb3 antagonists as pain therapeutics

Adrb3 拮抗剂作为疼痛治疗药物表征的测定方法开发

基本信息

批准号：
10287083
负责人：
Elaine Arrington Gay
金额：
$ 19.64万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287083
关键词：
3T3-L1 Cells Adenylate Cyclase Adipocytes Affect Affinity Analgesics Antidepressive Agents Binding Biological Assay Brown Fat Catechol O-Methyltransferase Catecholamines Cell Line Cells Chinese Hamster Ovary Cell Chronic Clinical Clinical Research Couples Cyclic AMP Data Development Enzymes Epinephrine Evaluation Family Fibromyalgia G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genes Goals Healthcare Human In Vitro Inflammation Inflammatory Irritable Bowel Syndrome Life Ligands Low Back Pain Measures Mediating Membrane Mesenchymal Stem Cells Metabolic Mitogen-Activated Protein Kinases Morphology Mus Nociceptors Norepinephrine Oils Opioid Oral Pain Pain management Patients Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphorylation Process Property Receptors, Adrenergic, beta-3 Rodent Second Messenger Systems Signal Transduction Site Solubility Specificity Spinal Stains Syndrome Temporomandibular Joint Disorders Testing Therapeutic Tissues Treatment Protocols Validation Ventilatory Depression Work addiction assay development base beta-adrenergic receptor chronic pain chronic pain management cytokine drug development drug discovery improved in vitro Assay knock-down member mental state novel p38 Mitogen Activated Protein Kinase preclinical study radioligand receptor side effect therapeutically effective tool

项目摘要

PROJECT SUMMARY Functional pain syndromes (FPS) affect over 100 million people, yet remain ineffectively treated by conventional pharmacotherapies, such as opioids, that have poor efficacy and adverse central side effects. Our long-term goal is to develop safer, more effective analgesics for patients with FPS, specifically peripherally-restricted antagonists of the beta-3 adrenergic receptor (Adrb3). The Adrb3 receptor is a G protein-coupled receptor that is activated by catecholamines. In clinical studies, we determined that patients with chronic FPS such as fibromyalgia, low back pain, and irritable bowel syndrome have increased levels of catecholamines alongside reduced levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, we have shown that pharmacologic inhibition of COMT in rodents produces pain at multiple body sites via activation of peripheral Adrb3. The pain is initiated by peripheral adipocyte Adrb3- mediated increases in pro-inflammatory cytokines in local tissues and maintained by subsequent increases in pro-inflammatory cytokines in spinal tissues and activation of mitogen activated protein kinases (MAPKs) in the cell bodies and central terminals of pain-sensing nociceptors. Thus, Adrb3 is a novel and attractive target for the treatment of chronic functional pain and pain-relevant inflammation. However, existing tool compounds either lack selectivity for Adrb3 or have poor metabolic properties. To successfully build a robust drug discovery platform for Abrb3 antagonists, in this proposal, we will develop and validate a battery of in vitro, cell-based assays to fully characterize the pharmacology of novel Adrb3 ligands. The development of high throughput, plate-based assays is critical for accurate evaluation of novel compound affinity, potency, efficacy, selectivity, and target validation, as part of a long-term medicinal chemistry campaign that seeks to produce new analgesics with improved specificity and side-effect profiles for the treatment of functional pain syndromes.

项目概要功能性疼痛综合征 (FPS) 影响着超过 1 亿人，但传统治疗方法仍然无效药物疗法，例如阿片类药物，其疗效较差且具有不良中枢副作用。我们的长期目标是为 FPS 患者（特别是外周受限患者）开发更安全、更有效的镇痛药 β-3 肾上腺素受体 (Adrb3) 拮抗剂。 Adrb3 受体是一种 G 蛋白偶联受体，被儿茶酚胺激活。在临床研究中，我们确定患有慢性 FPS 的患者，例如纤维肌痛、腰痛和肠易激综合征会导致儿茶酚胺水平升高儿茶酚-O-甲基转移酶（COMT；一种代谢儿茶酚胺的酶）水平降低。与临床综合征一致，我们已经证明，在啮齿类动物中，COMT 的药理抑制作用会产生通过激活外周 Adrb3 引起身体多个部位的疼痛。疼痛是由外周脂肪细胞Adrb3-引发的介导局部组织中促炎细胞因子的增加，并通过随后的增加来维持脊髓组织中的促炎细胞因子和丝裂原激活蛋白激酶（MAPK）的激活痛觉伤害感受器的细胞体和中央末端。因此，Adrb3 是一个新颖且有吸引力的靶点。治疗慢性功能性疼痛和疼痛相关炎症。然而，现有的工具组合要么对 Adrb3 缺乏选择性或代谢特性较差。成功建立强大的药物发现 Abrb3 拮抗剂平台，在本提案中，我们将开发并验证一系列体外、基于细胞的充分表征新型 Adrb3 配体的药理学特征的测定。发展高通量、基于平板的测定对于准确评估新型化合物的亲和力、效力、功效、选择性、和目标验证，作为旨在生产新镇痛药的长期药物化学活动的一部分具有改善功能性疼痛综合征治疗的特异性和副作用。