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: 8542812
• 负责人: Susruta Majumdar
• 金额: $ 21.41万
• 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/8542812
• 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.

描述（由申请人提供）：基于对其产生的启动子的启动子，可以将大量MU阿片受体（MOR-1）基因（MOR-1）基因（MOR-1）基因的剪接变体分为两组。主要启动子与外显子1相关，并产生大量传统的7个跨膜域受体。与外显子11相关的第二个启动子位于外显子1上游约30 kb，产生了许多截断的6个跨膜结构域。我们使用实验室中合成的新型放射性物体125i-bntxa，最近报道了一种新型的外显子11相关结合位点，在三kO小鼠中缺少所有外显子1-包含MOR-1拼接变体，以及Delta和Kappa1受体，在Exon 11 KO小鼠中丢失了。 IBNTXA是一种有效的镇痛药，其效力比吗啡高10倍。这种镇痛持续在三重KO小鼠中，但在外显子11 KO小鼠中丢失。尽管IBNTXA具有有效的镇痛作用，但仍缺乏呼吸抑郁症，重大便秘，身体依赖或奖励。它没有对吗啡的交叉耐受性，可以给予吗啡依赖性小鼠，而不会减少其自身的镇痛作用或戒断的沉淀。因此，该配体通过靶向截短的6个跨膜域剪接变体（6TM/e11），避免了传统阿片类药物看到的许多有问题的副作用。我建议将其用作铅化合物来设计阿片类镇痛药库。尽管具有良好的药理学，但对新目标的选择性比传统目标的选择性仅适度，并且可以改善。该项目的目的是获得选择性和有效的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化/分子药理学。类似物将包括基于Ibntxa的4,5-氧化甲型支架和Morphinan支架（4,5-5-氧化氧化甲型甲基氧气，缺乏空灵的氧气桥环A和C）。初步数据表明，在阿片类药物的6位处的芳基阿米多与芳基在芳基的3或4位置相结合的芳族可以增强对6TM/E11位点的亲和力。我们将探索具有各种取代基的4,5-氧化型支架的6个位置周围的化学空间。其他化合物包括第三级氮原子，14-OH上的取代基，以及使用芳基氨基甲氧摩尔苯并且具有双键在7,8位置之间的芳基。最后，也将合成芳基氨基甲虫。所有合成化合物都将使用体外放射性结合测定法进行选择性，并在体内评估有用的化合物。

项目成果

Isocyanide-Based Multicomponent Reactions for the Synthesis of Heterocycles.

• DOI: 10.3390/molecules21010019
• 发表时间: 2015-12-23
• 期刊: Molecules (Basel, Switzerland)
• 作者: Váradi A;Palmer TC;Notis Dardashti R;Majumdar S
• 通讯作者: Majumdar S

The antinociceptive effects of a dual kappa-delta opioid receptor agonist in the mouse formalin test.

双κ-δ阿片受体激动剂在小鼠福尔马林试验中的抗伤害作用。

• DOI: 10.1097/fbp.0000000000000541
• 发表时间: 2020
• 期刊: Behavioural pharmacology
• 影响因子: 1.6
• 作者: Ulker,Esad;Toma,Wisam;White,Alyssa;Uprety,Rajendra;Majumdar,Susruta;Damaj,MImad
• 通讯作者: Damaj,MImad

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder.

• DOI: 10.3389/fphar.2021.764885
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Gutridge AM;Chakraborty S;Varga BR;Rhoda ES;French AR;Blaine AT;Royer QH;Cui H;Yuan J;Cassell RJ;Szabó M;Majumdar S;van Rijn RM
• 通讯作者: van Rijn RM

Biased Opioid Ligands.

• DOI: 10.3390/molecules25184257
• 发表时间: 2020-09-16
• 期刊: Molecules (Basel, Switzerland)
• 作者: Faouzi A;Varga BR;Majumdar S
• 通讯作者: Majumdar S