Pharmacological Probes based on mitragynine pseudoindoxyl

基于帽柱木碱假吲哚酚的药理探针

• 批准号: 9765241
• 负责人: Susruta Majumdar
• 金额: $ 22.05万
• 依托单位: ST. LOUIS COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765241
• 关键词: Absence of pain sensation; Acrylates; Adverse effects; Affect; Affinity; Agonist; Alkaloids; Analgesics; Attenuated; Behavior; Binding; Biological Assay; Brain; C10; Cell Line; Chemicals; Clinical; Constipation; Cyclic AMP; Dangerousness; Dependence; Development; Dose; Drug Kinetics; Drug Prescriptions; Esters; Ethers; Exhibits; Fentanyl; G Protein-Coupled Receptor Signaling; GTP-Binding Proteins; Goals; Human; In Vitro; Indole Alkaloids; Inflammatory; Internet; Knockout Mice; Lead; Legal; Libraries; Liver Microsomes; Memorial Sloan-Kettering Cancer Center; Metabolic; Metabolism; Methods; Mitragyna; Molecular; Morphine; Morphine Derivatives Including Cocaine; Mus; Names; Natural Products; Neuropathy; Neurosciences; Opioid; Opioid Analgesics; Opioid Receptor; Opioid agonist; Oxycodone; Pain; Pain Measurement; Pain management; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physical Dependence; Plant Leaves; Positioning Attribute; Property; Reporting; Research; Rewards; Rodent; Rodent Model; Role; Societies; Solubility; Southeastern Asia; Structure; Structure-Activity Relationship; Synthesis Chemistry; System; Tail; Ventilatory Depression; addiction; analog; arrestin 2; base; behavioral pharmacology; beta-arrestin; chronic pain; design; drug metabolism; enol; experience; in vivo; mitragynine pseudoindoxyl; mu opioid receptors; novel; opioid use; pain model; pre-clinical; preference; programs; public health relevance; radioligand; receptor; scaffold; screening; side effect; treatment choice

Program Summary The ideal pain medication would be devoid of the serious side effects associated with the currently used opioids (respiratory depression, constipation, dependence, addiction). Mitragynine is a corynanthe-type indole alkaloid isolated as the major alkaloid component of the leaves of the plant Mitragyna speciosa; a “legal high” sold over the internet as kratom, and is currently unregulated. Mitragynine-related natural products possess affinity for mu opioid receptors and exhibit analgesia in rodent models when given systemically. Mitragynine pseudoindoxyl (MP), is a semi-synthetic analog related to mitragynine, which is more potent of an analgesic compared to mitragynine. This scaffold also behaves as delta antagonist, and as a biased mu agonist towards G-protein transduction systems. MP shows reduced respiratory depression, tolerance and dependence, and no rewarding behavior in mice. Thus, this template represents an excellent starting point for developing analgesics with a superior side effect profile to all clinically used mu opioid analgesics. We will also to create a library of derivatives of MP by using total and semi-synthetic approaches. Detailed pharmacological characterization of these analogs will lead to a substantially better understanding of SAR of MP-type compounds. Our final goal is to characterize the compounds pharmacologically in vitro and in vivo. Analogs will be evaluated for potency and an advantageous side-effect profile (i.e. absent or reduced tolerance, dependence, respiratory depression, constipation, reward and aversion). Physicochemical properties like solubility, stability, permeation and CNS penetration, also will be studied. The long-term objective of this proposal is to understand if G-biased MOR agonism in combination with DOR antagonism can lead to reduced tolerance/physical dependence in multiple rodent pain models (thermal, inflammatory, neuropathic) and also lead to synthesis of non-addicting and non-abusable analgesics. The central hypothesis is to diversify the MP template using our total synthetic/semi-synthetic approaches and prepare compounds with a MOR-DOR mixed agonist-antagonist profile with increased metabolic stability. These goals will be accomplished through an interdisciplinary team with significant experience in medicinal chemistry, synthetic chemistry, pharmacology, neuroscience, drug metabolism and pharmacokinetics.

程序摘要 理想的止痛药将没有与 目前使用的阿片类药物（呼吸抑制，便秘，依赖性，成瘾）。 Mitragynine是一种分离为Corynanthe型吲哚生物碱，分离为被分离为主要生物碱成分 植物Mitragyna Speciosa的叶子；通过互联网作为kratom出售的“法律高”，是 目前不受监管。与Mitragynine相关的天然产品具有对Mu Ooid的亲和力 当系统地给出时，啮齿动物模型中的受体和镇痛。 mitragynine 假毒基（MP）是与Mitragynine相关的半合成类似物，这是更多的潜力 与Mitragynine相比，镇痛药。这个脚手架也表现为三角洲拮抗剂， 偏向G蛋白转移系统的MU激动剂。 MP显示呼吸减少 抑郁症，耐受性和依赖性，没有小鼠的奖励行为。那，这个模板 代表了具有出色副作用曲线的镇痛药的绝佳起点 所有临床使用的MU阿片类镇痛药。我们还将通过 使用总和半合成方法。这些详细的药物表征 类似物将导致对MP型化合物SAR的次要理解。我们的 最终目标是在体外和体内对化合物进行表征。类似物会 可以评估效力和有利的副作用曲线（即不存在或减少 耐受性，依赖性，呼吸抑郁，便秘，奖励和厌恶）。 物理化学特性，例如溶解度，稳定性，渗透和CNS穿透，也将 研究。该提议的长期目标是了解G偏见的MOR激动剂是否 结合DOR拮抗作用可以导致耐受性/物理依赖性降低 多种啮齿动物疼痛模型（热，炎症，神经性疗法），也导致合成 不添加和不可动摇的镇痛药。中心假设是使MP多样化 使用我们的总合成/半合成方法的模板，并准备化合物 MOR-DOR混合激动剂 - 抗逆转肌曲线具有增加的代谢稳定性。这些目标将 可以通过具有丰富医疗经验的跨学科团队来完成 化学，合成化学，药理学，神经科学，药物代谢和 药代动力学。