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

• 批准号: 9113893
• 负责人: Jeffrey Aube
• 金额: $ 72.1万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113893
• 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; Clinical; 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; Injection of therapeutic agent; Lead; Ligands; Mediating; Mental Depression; Modeling; Molecular; Mood Disorders; Motor Activity; Neurologic; Neurons; Opioid; Opioid Receptor; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Property; Pruritus; Receptor Activation; Receptor Signaling; Recruitment Activity; Resources; Sedation procedure; Series; Signal Transduction; Staging; Stress; Structure; Sulfonamides; Time; Triazoles; Update; addiction; base; behavioral pharmacology; drug candidate; drug metabolism; dysphoria; improved; in vivo; insight; meetings; mouse model; novel; pharmacophore; pre-clinical; preclinical evaluation; prevent; public health relevance; receptor; receptor function; receptor sensitivity; response; scaffold; small molecule; therapeutic development; tool; transmission process

 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κ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，寻找KOR的负调节剂。有相当多的证据表明，KOR通过β抑制蛋白2介导某些副作用（镇静和烦躁），并通过G蛋白介导其镇痛和抗抑郁作用。因此，我们建议开发拮抗β抑制蛋白2相互作用受体的化合物。具体来说，我们的目标是提供：1。在抑制β抑制蛋白2募集方面是强效且有效的竞争性拮抗剂; 2.在阻断强啡肽刺激的β抑制蛋白2募集同时保留G蛋白信号传导中的完全激动作用方面具有有力竞争性的部分激动剂; 3.将降低KOR对强啡肽反应性的负变构调节剂。在这个建议中，我们提出了一个更新的广泛进展，我们已经在引入第一个小分子，G蛋白偏向KOR激动剂的领域。我们还提供了大量的初步数据，支持成功的运动，以开发上述拮抗剂，偏性部分激动剂和负变构调节剂。特别地，负变构调节剂将 成为这个受体的“第一人”该提案寻求5年的支持，以提供这些化合物的初始临床前表征和化学优化，使其成为候选药物。根据这一目标，我们将在功能多样的基于细胞的测定中充分表征化合物的药理学性质，目的是鉴定能够微调KOR反应性的化合物。将在小鼠模型中验证基于细胞的反应，评估运动反应、抗伤害感受活性和抑制皮炎（瘙痒反应），以确定化合物在体内保持药理学特征。将进行化合物的药物代谢和药代动力学研究，为持续的药物化学优化轮次提供信息，并将化合物推进临床开发。我们热情的团队由成熟的药物和合成化学家组成;阿片类药物神经药理学家（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专家。开发不同药效团的药理学工具并将其特性与体内反应谱相关联，将为产生所需生理反应所需的最佳化学和药理学特性提供指导性证据。