Parallel Multimodal High-throughput screening to identify activators of the orexin receptors
并行多模式高通量筛选鉴定食欲素受体激活剂
基本信息
- 批准号:10705475
- 负责人:
- 金额:$ 8.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-05 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
PROJECT SUMMARY
The GPCR superfamily of ligand regulated receptors has proven to be a rich source of targets for
development of therapeutics for a myriad of human diseases. The orexin 1 and orexin 2 receptors are class A
GPCR’s differentially expressed in the central nervous system. The orexin 1 receptor is most abundantly
expressed in the locus coeruleus and is thought to control aspects of emotion, reward, and the autonomic
nervous system, whereas the orexin 2 receptor is expressed in regions controlling arousal such as the
tubermammillary nucleus, an important site for the regulation of sleep/wakefulness. Almost 20 years after their
initial discovery, the first potent dual orexin 1 / orexin 2 receptor antagonist therapeutic has been brought to
market for insomnia (Belsomera ®, suvorexant, Merck). Despite a massive effort to identify antagonists of the the
orexin receptor, almost no reports of small molecule agonists appear in the primary or patent literature. Elegant
genetic ablation experiments using orexin knock-out animals and experiments with intracerebroventricular dosing
of orexin A or orexin B peptides suggests a role for orexin receptor agonists or potentiators for a number of potential
indications including: 1) depression; 2) learning and memory (cognition); 3) attention deficit hyperactivity disorder
(ADHD); 4) treatment for colon cancer; and 5) sleep disorders including narcolepsy. While the orexin peptides are
potent agonists of both orexin receptors, they are not selective nor do they cross the blood brain barrier well,
making them poor probe substrates for in vivo pharmacology studies. This provides the impetus to identify small
molecule, brain penetrant activators of the orexin receptors to interrogate the receptors function in the context of
disease states. We have optimized a cell-based high-throughput screening compatible primary assay that
specifically measures the functional activity of orexin 1 and orexin 2. A preliminary 10k pilot screen was
performed leading to the identification of a number of small molecule agonists of these receptors demonstrating
this assay to be robust and reproducible. A full HTS screening campaign of the Scripps Institutional Drug
Discovery Library (~640k compounds) will lead to the identification of multiple classes of orexin receptor agonists
and potentiators for further development. In an iterative process, these validated hits will be characterized
through a cascade of in vitro cell-based assays to determine potency, selectivity and mechanism of action.
Preliminary medicinal chemistry lead optimization will identify early structure activity relationships and in vitro
drug metabolism will be assessed to confirm tractibility of early leads. These efforts will provide first in-class
chemical tools to be used to further probe orexin receptor function in animal models of disease.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Theodore M Kamenecka其他文献
Theodore M Kamenecka的其他文献
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{{ truncateString('Theodore M Kamenecka', 18)}}的其他基金
Drug Discovery for First-In-Class Myosin 10 Inhibitors as a Novel Target for Glioblastoma
首创肌球蛋白 10 抑制剂作为胶质母细胞瘤新靶标的药物发现
- 批准号:
10355649 - 财政年份:2021
- 资助金额:
$ 8.25万 - 项目类别:
Drug Discovery for First-In-Class Myosin 10 Inhibitors as a Novel Target for Glioblastoma
首创肌球蛋白 10 抑制剂作为胶质母细胞瘤新靶标的药物发现
- 批准号:
10595848 - 财政年份:2021
- 资助金额:
$ 8.25万 - 项目类别:
Drug Discovery for First-In-Class Myosin 10 Inhibitors as a Novel Target for Glioblastoma
首创肌球蛋白 10 抑制剂作为胶质母细胞瘤新靶标的药物发现
- 批准号:
10704368 - 财政年份:2021
- 资助金额:
$ 8.25万 - 项目类别:
Development of novel therapeutics for opioid dependence
开发阿片类药物依赖的新疗法
- 批准号:
10209032 - 财政年份:2018
- 资助金额:
$ 8.25万 - 项目类别:
Parallel Multimodal High-throughput screening to identify activators of the orexin receptors
并行多模式高通量筛选鉴定食欲素受体激活剂
- 批准号:
9891102 - 财政年份:2018
- 资助金额:
$ 8.25万 - 项目类别:
Development of novel therapeutics for opioid dependence
开发阿片类药物依赖的新疗法
- 批准号:
10251366 - 财政年份:2018
- 资助金额:
$ 8.25万 - 项目类别:
Development of novel therapeutics for opioid dependence
开发阿片类药物依赖的新疗法
- 批准号:
10475113 - 财政年份:2018
- 资助金额:
$ 8.25万 - 项目类别:
Development of novel therapeutics for opioid dependence
开发阿片类药物依赖的新疗法
- 批准号:
9789248 - 财政年份:2018
- 资助金额:
$ 8.25万 - 项目类别:
Development of Orexin-1 Receptor Antagonists for Drug Addiction
用于治疗毒瘾的 Orexin-1 受体拮抗剂的开发
- 批准号:
8920528 - 财政年份:2012
- 资助金额:
$ 8.25万 - 项目类别:
Development of Orexin-1 Receptor Antagonists for Drug Addiction
用于治疗毒瘾的 Orexin-1 受体拮抗剂的开发
- 批准号:
9060913 - 财政年份:2012
- 资助金额:
$ 8.25万 - 项目类别:
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