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

• 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
• 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

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.

项目摘要 功能性疼痛综合征（FPS）影响超过1亿人，但仍被常规治疗无效治疗 药物疗法，例如阿片类药物，其功效差和中央副作用不良。我们的长期 目标是为FPS患者开发更安全，更有效的镇痛药，特别是外围限制性的 β-3肾上腺素能受体的拮抗剂（ADRB3）。 ADRB3受体是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，下腰痛和肠易激综合征的水平增加 儿茶酚-O-甲基转移酶的水平降低（COMT；一种代谢儿茶酚胺的酶）。 与临床综合征一致，我们已经表明，啮齿动物中COMT的药理抑制作用会产生 通过激活周围ADRB3在多个身体部位的疼痛。疼痛是由周围脂肪细胞ADRB3-引发的 局部组织中介导的促炎细胞因子的增加，并通过随后的增加而维持 脊柱组织中的促炎细胞因子和有丝分裂原活化蛋白激酶（MAPK）的激活 细胞体和疼痛感性伤害感受器的中央末端。因此，ADRB3是一个新颖而有吸引力的目标 治疗慢性功能性疼痛和疼痛相关的炎症。但是，现有的工具化合物要么 缺乏对ADRB3的选择性或代谢特性差。成功建立强大的药物发现 ABRB3拮抗剂的平台，在此提案中，我们将开发并验证一组体外，基于细胞的电池 实现新型ADRB3配体的药理学的测定。高吞吐量的发展， 基于板的测定对于准确评估新型复合亲和力，效力，功效，选择性，至关重要 和目标验证，作为一项长期药物化学运动的一部分，该运动旨在生产新的镇痛药 具有提高功能疼痛综合征治疗的特异性和副作用谱。