Pharmacological Probes based on mitragynine pseudoindoxyl

计划摘要 理想的止痛药应该是没有严重副作用的 目前使用的阿片类药物(呼吸抑制、便秘、依赖、成瘾)。 米特拉吉宁是一种鸡冠花型吲哚生物碱，分离出来的主要生物碱成分为米特拉宁。 这是一种在互联网上以KrATOM形式出售的“合法高价”，它是 目前不受监管。米拉吉宁相关天然产物对Mu阿片类药物具有亲和力 在啮齿动物模型中，当全身给药时，受体和表现出镇痛作用。米拉吉宁 伪吲哚(MP)，是一种与三尖杉碱有关的半合成类似物，它是一种更有效的 与米曲林相比是一种止痛药。该支架还起到了Delta拮抗剂的作用，并且 偏向于G蛋白转导系统的MU激动剂。MP显示呼吸减少 小鼠的抑郁、耐受和依赖，以及无奖赏行为。因此，该模板 为开发副作用更大的止痛药提供了一个极好的起点 所有临床上使用的阿片类止痛药。我们还将通过以下方式创建MP的衍生物库 使用完全和半合成的方法。这些药物的详细药理特征 类比将使我们更好地理解MP类化合物的SAR。我们的 最终目标是在体外和体内对这些化合物进行药理学表征。类比将会 评估药效和有利的副作用(即无副作用或减少副作用 耐受性、依赖性、呼吸抑制、便秘、奖励和厌恶)。 溶解性、稳定性、渗透性和中枢神经系统渗透性等物理化学性质也将 被研究。这项建议的长期目标是了解G-偏向MOR激动症 与DOR拮抗剂联合使用可导致耐受性/身体依赖性降低 多种啮齿动物疼痛模型(热的、炎性的、神经性的)，也导致合成 非上瘾和不可滥用的镇痛剂。核心假设是使国会议员多样化 使用我们的全合成/半合成方法制备模板，并制备具有 提高代谢稳定性的MOR-DOR混合激动剂-拮抗剂图谱。这些目标将 通过具有丰富医疗经验的跨学科团队完成 化学、合成化学、药理学、神经科学、药物代谢和 药物动力学。

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.