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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：
9891102
负责人：
Theodore M Kamenecka
金额：
$ 73.14万
依托单位：
SCRIPPS FLORIDA
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 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891102
关键词：
Ablation Agonist Animal Disease Models Animal Experiments Animal Model Arousal Arrestins Attention deficit hyperactivity disorder Automation Autonomic nervous system Binding Binding Proteins Biological Assay Blood - brain barrier anatomy Brain Brain region Cell Nucleus Cells Chemicals Chinese Hamster Ovary Cell Cognition Cyclic AMP Development Disease Dose Drug or chemical Tissue Distribution Emotions Family Family member Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genetic Goals In Vitro Investigation Lead Learning Legal patent Libraries Ligands Literature Malignant Neoplasms Measures Memory Mental Depression Miniaturization Mitogen-Activated Protein Kinase Kinases Narcolepsy Neuraxis Panic Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology Study Physiological Plasma Proteins Process Property Proteins Reporting Reproducibility Rewards Role Running Series Site Sleep Disorders Sleeplessness Solubility Source Specificity Structure-Activity Relationship System Testing Therapeutic Titrations Validation Wakefulness addiction base cheminformatics clinical development colon cancer treatment counterscreen cytotoxicity differential expression drug discovery drug metabolism experimental study high throughput screening human disease human model hypocretin in vivo knockout animal lead optimization locus ceruleus structure meetings miniaturize multimodality novel orexin 1 receptor orexin A orexin B orexin B receptor overexpression peptide B pharmacophore positive allosteric modulator radioligand receptor receptor function recruit release of sequestered calcium ion into cytoplasm screening sleep regulation small molecule therapeutic development therapeutic target tool

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