Analgesics targeting truncated 6transmembrane exon 11 variants of MOR-1 (6TM-E11)

针对 MOR-1 (6TM-E11) 截短的 6 跨膜外显子 11 变体的镇痛药

• 批准号: 8353038
• 负责人: Susruta Majumdar
• 金额: $ 22.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353038
• 关键词: Absence of pain sensation; Adverse effects; Affinity; Agonist; Amides; Amidone; Analgesics; Behavior; Binding; Binding Sites; Biochemical; Biochemistry; Biological Assay; Brain; Butorphanol; Chemicals; Constipation; Coupled; Data; Development; Electronics; Evaluation; Exons; Generations; Genes; Goals; In Vitro; Iodine; Label; Laboratories; Lead; Levorphanol; Libraries; Ligands; Longevity; Modification; Molecular; Morphinans; Morphine; Mus; Nitrogen; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Oxygen; Pain; Patients; Pharmacology; Pharmacotherapy; Physical Dependence; Positioning Attribute; Precipitation; Quality of life; RNA Splicing; Relative (related person); Reporting; Rewards; Site; Tail; Transmembrane Domain; Variant; Ventilatory Depression; Withdrawal; analog; base; chronic pain; design; flexibility; improved; in vivo; interest; mu opioid receptors; novel; pi bond; promoter; radioligand; receptor; scaffold; small molecule

DESCRIPTION (provided by applicant): The vast array of splice variants of mu opioid receptors (MOR-1) gene (Oprm1) can be divided into two groups based upon the promoters responsible for their generation. The primary promoter is associated with exon 1 and generates a large number of traditional 7 transmembrane domain receptors. The second promoter, associated with exon 11, located approximately 30 kb upstream of exon 1, generates a number of truncated, 6 transmembrane domains. Using a novel radioligand 125I-BNtxA synthesized in our laboratories, we recently reported a novel exon 11-associated binding site in a triple KO mouse lacking all exon 1- containing MOR-1 splice variants as well as delta and kappa1 receptors, that was lost in the exon 11 KO mice. IBNtxA is an effective analgesic, with a potency 10-fold greater than morphine. This analgesia persists in the triple KO mice, but is lost in the exon 11 KO mice. Despite it potent analgesic actions, IBNtxA lacks respiratory depression, significant constipation, physical dependence or reward. It shows no cross tolerance to morphine and can be given to morphine-dependent mice without a decrease in its own analgesic actions or the precipitation of withdrawal. Thus, this ligand avoids many of the problematic side-effects seen with traditional opioids by targeting truncated 6 transmembrane domain splice variants of the mu opioid receptor MOR-1(6TM/E11). I propose to use it as a lead compound to design a library of opioid analgesics. In spite of its favorable pharmacology, its selectivity for the new target over the traditional ones is only modest and can be improved. The goal of this project is to obtain selective and potent 6TM/E11 analgesics, establish an SAR and generate useful biochemical probes to study the biochemistry/molecular pharmacology of these sites. Analogs will include compounds based upon the 4,5-epoxymorphinan scaffold of IBNtxA and the morphinan scaffold (4,5-epoxymorphinans lacking the ethereal oxygen bridging rings A and C). Preliminary data suggests that an aryl amido at the 6-position of the opiate coupled with an iodine at the 3 or 4 position of the aryl enhances the affinity for the 6TM/E11 site. We will explore the chemical space around the 6 position of the 4,5-epoxymorphinan scaffold with various substituents. Other compounds include substituents on the tertiary nitrogen atom, the14-OH, and using aryl amido- epoxymorphinans with a double bond between 7,8 position. Finally, aryl amido-morphinans will also be synthesized. All synthesized compounds will be characterized for selectivity using in vitro radioligand binding assays and useful compounds will be evaluated in vivo. PUBLIC HEALTH RELEVANCE: Treatment of pain remains a major unmet need. Opiates continue to be useful pharmacotherapy for treatment of moderate to chronic pain but suffer from severe side effects that diminish the quality of life. The development of safe, effective and well tolerated pain medication without side-effects based on IBNtxA or other 6TM/E11-associated targets will be a major advancement in the treatment of pain that would greatly enhance both quality and length of life of patients both in the US and worldwide.

描述（由申请人提供）： mu 阿片受体（MOR-1）基因（Oprm1）的大量剪接变体可以根据负责其产生的启动子分为两组。初级启动子与外显子1相关，产生大量传统的7跨膜结构域受体。第二个启动子与外显子 11 相关，位于外显子 1 上游约 30 kb 处，产生许多截短的 6 个跨膜结构域。使用我们实验室合成的新型放射性配体 125I-BNtxA，我们最近在三重 KO 小鼠中报告了一个新的外显子 11 相关结合位点，该小鼠缺乏所有包含外显子 1 的 MOR-1 剪接变体以及 delta 和 kappa1 受体，该位点丢失在外显子 11 KO 小鼠中。 IBNtxA 是一种有效的镇痛药，其效力是吗啡的 10 倍。这种镇痛作用在三重 KO 小鼠中持续存在，但在外显子 11 KO 小鼠中消失。尽管 IBNtxA 具有有效的镇痛作用，但它缺乏呼吸抑制、严重便秘、身体依赖性或奖励。它对吗啡没有交叉耐受性，可以给予吗啡依赖的小鼠，而不会降低其自身的镇痛作用或导致戒断症状的沉淀。因此，该配体通过靶向 mu 阿片受体 MOR-1(6TM/E11) 的截短 6 跨膜结构域剪接变体，避免了传统阿片类药物所出现的许多有问题的副作用。我建议使用它作为先导化合物来设计阿片类镇痛药库。尽管其药理学良好，但与传统靶点相比，其对新靶点的选择性有限，并且可以改进。该项目的目标是获得选择性且有效的 6TM/E11 镇痛药，建立 SAR 并生成有用的生化探针来研究这些位点的生物化学/分子药理学。类似物将包括基于IBNtxA的4,5-环氧吗啡喃支架和吗啡喃支架（缺乏醚氧桥环A和C的4,5-环氧吗啡喃）的化合物。初步数据表明，阿片剂 6 位的芳基酰胺基与芳基 3 或 4 位的碘偶联可增强对 6TM/E11 位点的亲和力。我们将探索具有各种取代基的 4,5-环氧吗啡喃支架的 6 位周围的化学空间。其他化合物包括叔氮原子上的取代基，14-OH，并使用在7,8位之间具有双键的芳基酰胺基-环氧吗啡喃。最后，还将合成芳基酰胺基吗啡喃。所有合成的化合物将使用体外放射性配体结合测定来表征选择性，并且将在体内评估有用的化合物。 公共卫生相关性：疼痛治疗仍然是一个未满足的主要需求。阿片类药物仍然是治疗中度至慢性疼痛的有效药物疗法，但会产生严重的副作用，降低生活质量。基于 IBNtxA 或其他 6TM/E11 相关靶点开发安全、有效且耐受性良好且无副作用的止痛药物将是疼痛治疗的重大进步，将大大提高患者的生活质量和寿命。美国和全世界。