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（由适用提供）：我们建议开发新的Kappa阿片受体（KOR）调节剂，以提早开发以治疗添加剂和情绪障碍。 Dynorphins是压力性的，并在Kor上行动。因此，为了抑制大球介导的效应，感知了Kor的负调节剂。有大量证据表明，KOR通过βArrestin2信号介导某些副作用（镇静和吞咽困难）以及通过G蛋白来介导其镇痛和抗尿素作用。因此，我们建议开发拮抗βarrestin2相互作用受体的化合物。具体而言，我们旨在交付：1。在抑制βArrestin2招募方面具有潜在和有效的竞争性拮抗剂； 2。部分拮抗剂，在阻断dynorphin刺激的βarrestin2募集的同时保留G蛋白信号传导中的全部激动剂时具有潜在竞争力； 3.负变构调节剂，将降低对Dynorphins的反应。在此提案中，我们介绍了我们在将第一个小分子G蛋白偏向于该领域引入第一个小分子的广泛进展的最新信息。我们还提供了实质性的初步数据，该数据支持成功的运动，以发展早期的对手，偏见的部分激动剂和负变态调节剂。特别是，负性变构调节器将对于此接收器，要“在课堂上”。该提案寻求5年的支持，以将这些化合物的最初临床前特征和化学优化提供为候选药物。与这个目标一致，我们将充分表征在功能多样的基于细胞的评估中TH化合物的药物特性，其目标是识别能够微调KOR响应能力的化合物。基于细胞的反应将在小鼠模型评估运动反应，抗吸引性活性和抑制瘙痒症（瘙痒反应）中进行验证，以确定化合物在体内维持药物特征。将对化合物的药物代谢和药代动力学进行，以提供持续的医学化学优化回合的信息，并将化合物推向临床发育。我们的Anthuesian团队由既定的医学和合成化学家组成；阿片类神经药物学家（具有分子和行为药理学专业知识）；以及药代动力学和药物代谢的专家。跨潜水员药理的药物工具的开发，并将其特性与体内反应曲线相关联，将为产生所需物理反应所需的最佳化学和药理特性提供指导证据。

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。