Development of Adrb3 Antagonists for the Treatment of Pain

用于治疗疼痛的 Adrb3 拮抗剂的开发

基本信息

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
项目类别：
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

项目摘要

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.

项目概要慢性原发性疼痛 (CPPC) 影响着超过 1 亿人，但仍无法有效治疗传统的药物疗法，例如阿片类药物，疗效不佳且具有不良中枢副作用。这该提案的目标是为 CPPC 患者开发更安全、更有效的镇痛药。具体来说，我们将开发有效的、选择性的、外周限制性的肾上腺素受体 β-3 (Adrb3) 拮抗剂。 Adrb3 是一种由儿茶酚胺激活的 G 蛋白偶联受体。在临床研究中，我们确定患者患有纤维肌痛、腰痛和肠易激综合征等 CPPC 的人，儿茶酚胺以及儿茶酚-O-甲基转移酶（COMT；一种代谢酶）水平降低儿茶酚胺）。与临床发现一致，我们的实验室已表明遗传或药物抑制啮齿动物中的 COMT 通过儿茶酚胺激活 Adrb3 及其下游在多个身体部位产生疼痛促进炎症并增加炎症反应的效应物（例如细胞因子和 p38 丝裂原激活蛋白激酶）痛觉伤害感受器的活动。因此，Adrb3是治疗慢性疾病的一个新颖且有吸引力的靶点。原发性疼痛。然而，Adrb3 的拮抗工具化合物仅有少数，甚至是最有效和选择性最强的我们的初步药代动力学研究表明，拮抗剂 L-748,336 的代谢特性较差。此外，还需要开展更多工作来确定 Adrb3 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 Adrb3 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支架开发新型Adrb3拮抗剂改进的效力、类药特性和外周选择性，2) 测试 L-748,337 和新的能力合成的 Adrb3 拮抗剂可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），以及3）建立一支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，以将我们的先导化合物发展为成功的 U19 疗法发现平台。成功完成这些研究将导致新的开发外周限制性镇痛药，适合进入人体试验，有潜力对数百万慢性原发性疼痛患者的生活质量产生积极影响。