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）：μ阿片受体（莫尔-1）基因（Oprm 1）的大量剪接变体可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，并产生大量传统的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125 I-BNtxA，我们最近报道了一种新型外显子11相关结合位点，该位点在缺失所有含外显子1的莫尔-1剪接变体以及δ和κ 1受体的三重KO小鼠中缺失。IBNtxA是一种有效的镇痛剂，其效力比吗啡大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、身体依赖性或奖赏。它对吗啡无交叉耐受性，可用于吗啡依赖小鼠而不降低其自身的镇痛作用或沉淀戒断反应。因此，该配体通过靶向μ阿片受体莫尔-1（6 TM/E11）的截短的6跨膜结构域剪接变体，避免了传统阿片类药物所见的许多有问题的副作用。我建议用它作为先导化合物来设计一个阿片类镇痛药库。尽管其具有良好的药理学作用，但其对新靶点的选择性相对于传统靶点而言仅是适度的，并且可以改进。本项目的目标是获得选择性和有效的6 TM/E11镇痛药，建立SAR和产生有用的生化探针，研究这些网站的生物化学/分子药理学。类似物将包括基于IBNtxA的4，5-环氧吗啡喃骨架和吗啡喃骨架（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，在阿片剂的6-位的芳基酰胺基与在芳基的3或4位的碘偶联增强了对6 TM/E11位点的亲和力。我们将探索具有各种取代基的4，5-环氧吗啡喃支架的6位周围的化学空间。其它化合物包括取代基上的叔氮原子、14-OH、和使用芳基酰胺基-环氧吗啡烷与双键之间的7、8位。最后，还将合成芳基酰胺-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，并且将在体内评价有用的化合物。

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