Development of Adrb3 Antagonists for the Treatment of Pain

用于治疗疼痛的 Adrb3 拮抗剂的开发

• 批准号: 10730831
• 负责人: Chunyang Jin
• 金额: $ 184.62万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730831
• 关键词: 3T3-L1 Cells; Adipocytes; Adrenergic Antagonists; Adverse effects; Affect; Analgesics; Antidepressive Agents; Binding; Biological Assay; Biology; Brain; Cardiac; Catechol O-Methyltransferase; Catecholamines; Cell Line; Cells; Central Nervous System; Chronic; Clinical; Clinical Research; Clinical Trials; Communication; Complement; Computer Analysis; Cyclic AMP; Data; Development; Drug Kinetics; Electronics; Enzymes; Event; Fibromyalgia; Funding; G-Protein-Coupled Receptors; Genetic; Genetic Predisposition to Disease; Goals; Healthcare; Homology Modeling; Human; In Vitro; Inflammation; Infrastructure; Irritable Bowel Syndrome; Knock-out; Lead; Life; Low Back Pain; Metabolic; Modeling; Modification; Mus; Neuroglia; Nociceptors; Opioid; Oral; Pain; Pain management; Patient advocacy; Patients; Penetration; Peripheral; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Propanolamines; Property; Quality of life; Receptors, Adrenergic, beta-3; Regulation; Rodent; Series; Site; Solubility; Specificity; Spinal Cord; Syndrome; Temporomandibular Joint Disorders; Testing; Therapeutic; Treatment Protocols; Ventilatory Depression; Work; addiction; addiction liability; analog; antagonist; antinociception; calcium indicator; chronic pain; chronic pain management; clinical pain; clinical translation; commercialization; comorbidity; cytokine; data management; depressive behavior; design; drug development; drug discovery; improved; in vivo; in vivo calcium imaging; meetings; mental state; mouse model; multidisciplinary; novel; p38 Mitogen Activated Protein Kinase; pain behavior; pain model; pharmacologic; pharmacophore; pre-clinical assessment; preclinical study; prevent; radioligand; receptor; relational database; scaffold; side effect; therapeutic development; tool; urinary

PROJECT SUMMARY Chronic primary pain conditions (CPPCs) affect over 100 million people, yet remain ineffectively treated by conventional pharmacotherapies, such as opioids, that have poor efficacy and adverse central side effects. The goal of this proposal is to develop safer, more effective analgesics for patients with CPPCs. Specifically, we will develop potent, selective, peripherally-restricted antagonists of the adrenergic receptor beta-3 (Adrb3). Adrb3 is a G protein-coupled receptor that is activated by catecholamines. In clinical studies, we determined that patients with CPPCs 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 findings, our lab has shown that genetic or pharmacologic inhibition of COMT in rodents produces pain at multiple body sites via catecholamine activation of Adrb3 and its downstream effectors (eg, cytokines and p38 mitogen activated protein kinase) that promote inflammation and increase activity of pain-sensing nociceptors. Thus, Adrb3 is a novel and attractive target for the treatment of chronic primary pain. Yet, only a few antagonist tool compounds for Adrb3 exist, and even the most potent and selective antagonist L-748,336 has poor metabolic properties as identified by our preliminary pharmacokinetic studies. Further, additional work is needed to determine the ability of Adrb3 antagonists to reverse chronic primary pain. Thus, our objective is to develop a drug discovery platform for Adrb3 antagonists. To accomplish this, we propose to 1) develop novel Adrb3 antagonists based on the existing aryloxy propanolamine scaffold in L-748,337 with improved potency, drug-like properties, and peripheral selectivity, 2) test the ability of L-748,337 and newly synthesized Adrb3 antagonists to reverse COMT-dependent pain and nociceptor activity in the absence of side- effects (eg, addiction, cardiac, urinary), and 3) develop a multidisciplinary team with expertise in pain biology, medicinal chemistry, and drug development, regulation, and commercialization as well as clinical pain management, clinical trials, and patient advocacy to progress our lead-like compounds to a successful U19 therapeutics discovery platform. Successful completion of these studies will lead to the development of new peripherally-restricted analgesics that are suitable for advancement into human trials with the potential to have a positive impact on the quality of life for the millions who suffer from chronic primary pain.

项目摘要 慢性原发性疼痛状况（CPPC）影响超过1亿人，但仍然无法有效治疗， 常规药物治疗，如阿片类药物，疗效差，有不良的中枢副作用。的 该提案的目标是为CPPC患者开发更安全、更有效的镇痛药。具体来说，我们将 开发肾上腺素能受体β-3（Adrb 3）的强效、选择性、外周限制性拮抗剂。Adrb 3是 一种被儿茶酚胺激活的G蛋白偶联受体。在临床研究中，我们确定患者 与CPPC，如纤维肌痛，腰痛，肠易激综合征的水平增加， 儿茶酚-O-甲基转移酶（COMT;一种代谢 儿茶酚胺）。与临床结果一致，我们的实验室已经表明，遗传或药理学抑制 啮齿类动物的COMT通过肾上腺素受体3及其下游的儿茶酚胺激活在多个身体部位产生疼痛 促进炎症和增加细胞因子和p38丝裂原活化蛋白激酶的效应物 疼痛感受器的活动。因此，Adrb 3是一种新的和有吸引力的治疗慢性炎症的靶点。 原发性疼痛然而，仅存在少数Adrb 3的拮抗剂工具化合物，并且即使是最有效和选择性的 拮抗剂L-748，336具有差的代谢特性，如我们的初步药代动力学研究所鉴定的。 此外，还需要进一步的工作来确定Adrb 3拮抗剂逆转慢性原发性疼痛的能力。 因此，我们的目标是开发Adrb 3拮抗剂的药物发现平台。为了实现这一目标，我们建议 1）基于L-748，337中现有的芳氧基丙醇胺骨架开发新的Adrb 3拮抗剂， 改进的效力、药物样性质和外周选择性，2）测试L-748，337和新的 合成的Adrb 3拮抗剂在没有副作用的情况下逆转COMT依赖性疼痛和伤害感受器活性， 影响（例如，成瘾，心脏，泌尿），和3）发展一个具有疼痛生物学专业知识的多学科团队， 药物化学，药物开发，监管和商业化以及临床疼痛 管理，临床试验和患者宣传，以使我们的铅样化合物成功用于U19 治疗发现平台。这些研究的成功完成将导致新的发展 适合进入人体试验的外周限制性镇痛药，有可能 对数百万慢性原发性疼痛患者的生活质量产生积极影响。