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Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology

Kappa 阿片受体的新型探针：化学、药理学和生物学

基本信息

批准号：
9889913
负责人：
Jeffrey Aube
金额：
$ 63.8万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889913
关键词：
Acute Adverse effects Affinity Agonist Analgesics Animal Model Antipruritic Effect Behavior Biological Biological Assay Biological Availability Biology Brain Cells Chemicals Chemistry Chronic Data Deposition Depressed mood Development Dopamine Dopamine Receptor Drug Exposure Drug Kinetics Drug Targeting Drug abuse Dynorphins Evaluation Florida Funding G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Proteins Goals Hour In Vitro Injections Lead Ligands Mediating Mental Depression Modeling Molecular Mood Disorders Motor Activity Neurologic Neurons Opioid Opioid agonist Pathway interactions Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Property Pruritus Receptor Activation Receptor Signaling Resources Sedation procedure Series Signal Transduction Signaling Protein Stress Structure Sulfonamides Time Triazoles Update addiction base behavioral pharmacology clinical development drug candidate drug metabolism dysphoria improved in vivo insight kappa opioid receptors meetings mouse model novel pharmacophore pre-clinical preclinical evaluation preservation prevent public health relevance receptor receptor function receptor sensitivity recruit response scaffold side effect small molecule therapeutic development tool transmission process

项目摘要

DESCRIPTION (provided by applicant): We propose to develop new kappa opioid receptor (KOR) modulators for early stage development towards treating addictive and mood disorders. Dynorphins are stress peptides and act at the KOR. Therefore, to suppress dynorphin-mediated effects, negative regulators of KOR are sought. There is considerable evidence that KOR signals through βarrestin2 to mediate certain side effects (sedation and dysphoria) and through G proteins to mediate its analgesic and antipruritic effects. Therefore, we propose to develop compounds that antagonize the βarrestin2-interacting receptor. Specifically we aim to deliver: 1. Competitive antagonists that are potent and efficacious in suppressing βarrestin2 recruitment; 2. Partial agonists that are potently competitive at blocking dynorphin-stimulated βarrestin2 recruitment while preserving full agonism in G protein signaling; 3. Negative allosteric modulators that will decrease KOR responsiveness to dynorphins. In this proposal, we present an update on the extensive progress we have made in introducing the first small molecule, G protein biased KOR agonists to the field. We also provide substantial preliminary data supporting a successful campaign to develop the aforementioned antagonists, biased partial agonists and negative allosteric modulators. In particular, the negative allosteric modulators will be "first in class" for this receptor. This proposal seeks 5 years of support to provide the initia preclinical characterizations and chemical optimizations of these compounds into drug candidates. In line with this goal, we will fully characterize the pharmacological properties of th compounds across functionally diverse cell-based assays with of a goal of identifying compounds capable of fine-tuning KOR responsiveness. Cell-based responses will be validated in mouse models assessing locomotor responses, antinociceptive activity and suppressing pruritis (itch response) to determine that compound maintains the pharmacological profiles in vivo. Drug metabolism and pharmacokinetics of the compounds will be performed to provide information for continued medicinal chemistry optimization rounds and to advance compounds to clinical development. Our enthusiastic team consists of established medicinal and synthetic chemists; an opioid neuropharmacologist (with both molecular and behavioral pharmacology expertise); and an expert in pharmacokinetics and drug metabolism. The development of pharmacological tools across diverse pharmacophores and correlating their properties with in vivo response profiles will provide guiding evidence of the optimal chemical and pharmacological properties required to produce the desired physiological responses.

描述（由申请人提供）：我们建议开发新的 kappa 阿片受体（KOR）调节剂，用于治疗成瘾和情绪障碍的早期开发。强啡肽是应激肽，作用于 KOR。因此，为了抑制强啡肽介导的作用，需要寻找 KOR 的负调节因子。有大量证据表明，KOR 通过 βarrestin2 发出信号来介导某些副作用（镇静和烦躁不安），并通过 G 蛋白来介导其镇痛和止痒作用。因此，我们建议开发拮抗 βarrestin2 相互作用受体的化合物。具体来说，我们的目标是提供： 1. 竞争性拮抗剂，能够有效抑制 βarrestin2 募集； 2. 部分激动剂可有效竞争性阻断强啡肽刺激的 βarrestin2 募集，同时保留 G 蛋白信号传导的完全激动作用； 3. 负变构调节剂会降低 KOR 对强啡肽的反应性。在本提案中，我们介绍了我们在将第一个小分子 G 蛋白偏向 KOR 激动剂引入该领域所取得的广泛进展的最新情况。我们还提供了大量的初步数据，支持成功开发上述拮抗剂、偏向部分激动剂和负变构调节剂的活动。特别是，负变构调节剂将成为该受体的“一流”。该提案寻求 5 年的支持，为候选药物提供这些化合物的初始临床前表征和化学优化。根据这一目标，我们将通过功能多样的基于细胞的测定来全面表征该化合物的药理学特性，目标是识别能够微调 KOR 响应性的化合物。基于细胞的反应将在评估运动反应、抗伤害活性和抑制瘙痒（瘙痒反应）的小鼠模型中得到验证，以确定该化合物在体内维持药理学特征。将进行化合物的药物代谢和药代动力学分析，为持续的药物化学优化轮次提供信息，并推动化合物进入临床开发。我们热情的团队由资深的药物和合成化学家组成；阿片类神经药理学家（具有分子和行为药理学专业知识）；药代动力学和药物代谢方面的专家。跨不同药效团的药理学工具的开发以及将其特性与体内反应曲线相关联将为产生所需的生理反应所需的最佳化学和药理学特性提供指导证据。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif.

DOI：
10.1016/j.bmc.2014.12.033
发表时间：
2015-07-15
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Frankowski KJ;Slauson SR;Lovell KM;Phillips AM;Streicher JM;Zhou L;Whipple DA;Schoenen FJ;Prisinzano TE;Bohn LM;Aubé J
通讯作者：
Aubé J

Synthesis of Kappa Opioid Antagonists Based On Pyrrolo[1,2-α]quinoxalinones Using an N-Arylation/Condensation/Oxidation Reaction Sequence.

使用 N-芳基化/缩合/氧化反应序列合成基于吡咯并[1,2-α]喹喔啉酮的 Kappa 阿片拮抗剂。