Pharmacological Probes based on mitragynine pseudoindoxyl

基于帽柱木碱假吲哚酚的药理探针

基本信息

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
项目类别：
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

项目摘要

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.

计划概要理想的止痛药应避免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、依赖性、成瘾）。帽柱木碱是一种棒状吲哚生物碱，作为帽柱木碱的主要生物碱成分被分离出来。 Mitragyna spiosa 植物的叶子；一种“合法的兴奋剂”，在互联网上以 kratom 的形式出售，并且是目前不受管制的帽柱木碱相关天然产物对 mu 阿片类药物具有亲和力。受体并在啮齿动物模型中全身给予帽柱木碱时表现出镇痛作用。假吲哚酚 (MP) 是一种与帽柱木碱相关的半合成类似物，其作用更有效与帽柱木碱相比，该支架还具有 δ 拮抗剂的作用。偏向于 G 蛋白转导系统的 mu 激动剂显示呼吸减少。小鼠的抑郁、耐受性和依赖性以及无奖励行为。代表了开发具有优异副作用的镇痛药的绝佳起点我们还将创建一个 MP 衍生物库。使用全合成和半合成方法对这些药物进行详细的药理学表征。类似物将导致我们对 MP 型化合物的 SAR 有了更好的理解。最终目标是在体外和体内表征化合物的药理学。评估效力和有利的副作用（即不存在或减少）耐受性、依赖性、呼吸抑制、便秘、奖励和厌恶）。物理化学特性，如溶解度、稳定性、渗透性和中枢神经系统渗透性，也会该提案的长期目标是了解 G 偏向的 MOR 激动作用。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、炎性、神经性），并且还导致合成中心假设是使 MP 多样化。使用我们的全合成/半合成方法模板并用化合物a制备 MOR-DOR 混合激动剂-拮抗剂特性具有更高的代谢稳定性。通过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。