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.

节目概要 理想的止痛药应该没有与止痛药相关的严重副作用。 目前使用的阿片类药物（呼吸抑制、便秘、依赖、成瘾）。 Mitragynine是一种紫堇型吲哚生物碱，作为其主要生物碱成分分离。 植物Mitragyna speciosa的叶子;一种“法律的高”在互联网上作为kratom出售， 目前不受管制。Mitragynine相关天然产物对μ阿片类药物具有亲和力 受体，并且当全身给药时在啮齿动物模型中表现出镇痛作用。紫穗槐碱 假吲哚酚（MP）是一种与mitragynine相关的半合成类似物，其比mitragynine更有效。 一种止痛药该支架还表现为δ拮抗剂，并且作为 一种偏向G蛋白转导系统的μ激动剂。MP显示呼吸减少 抑郁、耐受和依赖，无奖励行为。因此，该模板 代表了开发具有上级副作用特征的镇痛药的良好起点 所有临床使用的μ阿片类镇痛药。我们还将创建一个MP衍生物库， 使用全合成和半合成方法。这些药物的详细药理学特征 类似物将导致更好地理解MP型化合物的SAR。我们 最终目标是表征在体外和体内可降解的化合物。类似物将 评价效力和有利的副作用特征（即不存在或减少 耐受性、依赖性、呼吸抑制、便秘、奖赏和厌恶）。 物理化学性质，如溶解性、稳定性、渗透性和CNS渗透性，也将 被研究。本提案的长期目标是了解G偏置莫尔激动是否 与DOR拮抗作用结合可导致耐受性/身体依赖性降低， 多种啮齿动物疼痛模型（热，炎症，神经性），也导致合成 非成瘾性和不可滥用的镇痛剂。核心假设是使国会议员多样化 模板使用我们的全合成/半合成方法，并制备具有 MOR-DOR混合激动剂-拮抗剂特征，代谢稳定性增加。这些目标将 通过一个具有丰富医学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