Optimization of MrgX1 allosteric agonists as potential therapies for chronic pain

MrgX1 变构激动剂的优化作为慢性疼痛的潜在疗法

• 批准号: 10112868
• 负责人: Corey R. Hopkins
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112868
• 关键词: Adverse effects; Affective; Afferent Neurons; Agonist; Analgesics; Back; Binding; Binding Proteins; Biological Assay; Brain; Caliber; Cellular Assay; Characteristics; Clinical; Data; Development; Dose; Dose-Limiting; Drug Kinetics; Equilibrium; Family; Funding; Future; G-Protein-Coupled Receptors; Goals; Grant; Health; Homologous Gene; Human; In Vitro; Intervention; Lead; Ligation; Measures; Medicine; Modeling; Mus; Neuraxis; Neurons; Nociceptors; Opioid; Oral; Orphan; Pain; Pathway interactions; Penetration; Permeability; Persistent pain; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Plasma Proteins; Play; Positioning Attribute; Property; Research; Risk; Role; Signal Transduction; Skin; Solubility; Spinal Ganglia; Spinal nerve structure; Testing; Toxicology; Viscera; Work; addiction; analog; chemical synthesis; chronic constriction injury; chronic pain; conditioned place preference; design; efficacy evaluation; experience; health economics; improved; in vivo; in vivo evaluation; lead optimization; meetings; member; mouse model; novel; pain model; pharmacokinetics and pharmacodynamics; pre-clinical; programs; receptor; scaffold; side effect; spontaneous pain; tool; transmission process

Chronic pain is a major health and economic problem worldwide. Because the major analgesics (e.g., opioids) bind to receptors that are widely expressed throughout the central nervous system (CNS), dose-limiting adverse effects and significant risk of addiction and abuse present substantial barriers to their clinical use. Pain sensing neurons (a.k.a nociceptors) in dorsal root ganglion (DRG) play essential role in pain transmission by detecting painful signals in the periphery such as skin and viscera. Therefore, targeting molecules specifically expressed in nociceptors may offer an opportunity for pain-selective pharmacologic interventions. Our previous data have shown that Mrgs including mouse MrgC11 and human MrgX1 are specifically expressed in nociceptors in DRG and constitute an endogenous anti-pain pathway. Funded R03 grant allowed us to identify selective and potent MrgX1 allosteric agonists. Preliminary data showed that two allosteric agonists inhibited persistent pain in humanized MrgX1 mice. MrgX1 allosteric agonists may potentially become novel anti-chronic pain drugs with limited CNS-related side effects. In this proposal, we will improve and optimize MrgX1 allosteric agonists and test their analgesic efficacy in mice. Highly selective agonists, and for the purpose of this proposal, allosteric agonists, are needed in order to better understand the respective role of MrgX1 in these studies of chronic pain. We have recently discovered a novel class of allosteric agonists with potency on MrgX1 and selectivity against MrgX2. These selective allosteric agonists offer a unique opportunity to test the hypothesis presented in this proposal. In order to develop first-in-class, potent, selective and CNS penetrant MrgX1 allosteric agonists, we will optimize our lead scaffold such that the tool compound will possess the appropriate properties, a balance of potency, selectivity and DMPK. We will utilize an iterative medicinal chemistry approach which will enable all of the attributes to be evaluated in parallel. Once the tool compound(s) have been determined, we will then test these compounds in the humanized MrgX1 mouse model.

慢性疼痛是世界范围内的一个主要健康和经济问题。因为主要的镇痛药（如阿片类药物）

项目成果

Synthesis and Biological Characterization of a Series of 2-Sulfonamidebenzamides as Allosteric Modulators of MrgX1.

作为 MrgX1 变构调节剂的一系列 2-磺酰胺苯甲酰胺的合成和生物学表征。

• DOI: 10.1021/acsmedchemlett.2c00100
• 发表时间: 2022
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Sharma,Swagat;Peng,Qi;Vadukoot,AnishK;Aretz,ChristopherD;Jensen,AaronA;Wallick,AlexanderI;Dong,Xinzhong;Hopkins,CoreyR
• 通讯作者: Hopkins,CoreyR