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: 8869092
• 负责人: Susruta Majumdar
• 金额: $ 29.98万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869092
• 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; public health relevance; radioligand; receptor; scaffold; small molecule

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.

μ阿片受体（莫尔-1）基因（Oprm 1）的大量剪接变体可分为 根据负责其产生的启动子分为两组。主 启动子与外显子1相关，并产生大量传统的7 跨膜区受体。第二个启动子，与外显子11相关，位于 外显子1上游约30 kb，产生许多截短的6个跨膜 域.利用我们实验室合成的新型放射性配体125 I-BNtxA， 报道了一种新的外显子11相关的结合位点在三重敲除小鼠缺乏所有外显子1- 含有莫尔-1剪接变体以及δ和卡帕1受体，该受体在细胞中丢失 外显子11 KO小鼠。IBNtxA是一种有效的止痛剂，其效力是IBNtxA的10倍。 吗啡这种镇痛作用在三重KO小鼠中持续存在，但在外显子11 KO小鼠中丧失。 尽管IBNtxA具有有效的镇痛作用，但它缺乏呼吸抑制，显著的便秘， 身体依赖或奖励。它对吗啡无交叉耐受性， 吗啡依赖小鼠，其自身的镇痛作用没有减少， 戒断因此，这种配体避免了传统配体中出现的许多问题副作用 通过靶向μ阿片样物质的截短的6个跨膜结构域剪接变体的阿片样物质 受体莫尔-1（6 TM/E11）。我建议用它作为先导化合物来设计一个阿片类药物库 止痛药尽管其具有良好的药理学作用，但其对新靶点的选择性超过对靶点的选择性。 传统的方法是有限的，可以改进。该项目的目标是获得 选择性和有效的6 TM/E11镇痛剂，建立SAR并产生有用的生化 研究这些位点的生物化学/分子药理学的探针。类比将包括 基于IBNtxA的4，5-环氧吗啡喃骨架和吗啡喃骨架的化合物 （缺少醚氧桥环A和C的4，5-环氧吗啡喃）。初步数据 表明在阿片剂的6位上的芳基酰胺基与在3或4位上的碘偶联， 芳基的位置增强了对6 TM/E11位点的亲和力。我们将探索 具有各种取代基的4，5-环氧吗啡喃骨架的6位周围的空间。其他 化合物包括叔氮原子上的取代基，14-OH，并使用芳基酰胺基- 在7，8位之间具有双键的环氧吗啡烷。最后，芳基氨基吗啡烷将 也可以合成。所有合成的化合物都将使用以下方法表征选择性： 体外放射性配体结合测定和有用的化合物将在体内进行评价。