Molecular Characterization of GPR35 and GPR55, Putative Cannabinoid Receptors

GPR35 和 GPR55（假定的大麻素受体）的分子表征

• 批准号: 8296972
• 负责人: MARY E ABOOD
• 金额: $ 30.9万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296972
• 关键词: Affinity; Agonist; Amino Acids; Animal Model; Area; Arrestins; Asthma; Binding; Biological Assay; Bone Development; Calcium; Cannabinoids; Cells; Development; Drug Receptors; Drug abuse; Exhibits; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Heart Diseases; Inflammatory Bowel Diseases; Label; Ligands; MAP Kinase Gene; Malignant Neoplasms; Measures; Metabolic Diseases; Modeling; Molecular; Molecular Conformation; Molecular Models; Molecular Profiling; Mutation; Names; Nature; Orphan; Pain; Perception; Phosphotransferases; Physiological; Receptor Activation; Screening Result; Signal Transduction; Signal Transduction Pathway; Site-Directed Mutagenesis; Spinal; Structure; Structure-Activity Relationship; Techniques; addiction; base; beta-arrestin; cannabinoid receptor; cheminformatics; counterscreen; design; drug of abuse; high throughput screening; improved; inflammatory pain; interest; molecular modeling; mutant; painful neuropathy; protein activation; radioligand; receptor; receptor internalization; research study; scaffold; tool; trafficking

DESCRIPTION (provided by applicant): Many G-protein coupled receptors involved in pain and addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 and GPR55, with homology to known receptors for drugs of abuse, remain poorly characterized. GPR55 is emerging as an important target in inflammatory pain, neuropathic pain, and bone development while other studies indicate that GPR55 activation is pro-carcinogenic. GPR55 does recognize certain cannabinoid ligands, so it has been suggested to be a third cannabinoid receptor. GPR35 is an important target in pain (spinal antinociception as well as inflammatory pain), heart disease, asthma, metabolic disease, inflammatory bowel disease and cancer. Each of these areas alone is medically important and each would benefit by the use of selective agonists and antagonists to further studies in their respective animal models. However, to date, no low nanomolar potency ligands have been discovered for these receptors nor is there a radioligand developed to characterize binding. The lack of such ligands is a critical barrier to progress in this field. The goal of this proposal is to leverage our recen promising high throughput, high content screening results for GPR55 agonists and GPR35 antagonists using structure based design and cheminformatics tools to develop an SAR for selected scaffolds that leads to the identification of low nanamolar ligands that retain high receptor selectivity. We aim to discover nanomolar potency GPR55 and GPR35 ligands using a combination of structure-based design, molecular modeling, chemoinformatics, high-throughput screening and site directed mutagenesis. PUBLIC HEALTH RELEVANCE: Many G-protein coupled receptors involved in pain and addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 and GPR55, with homology to known receptors for drugs of abuse, remain poorly characterized. Both GPR55 and GPR35 are emerging as important targets in inflammatory pain, cancer and metabolic disease, to name a few. However, the lack of potent agonists and antagonists for these receptors are a critical barrier to progress this field. The goa of this proposal is to leverage our recent promising high throughput screening results for GPR55 agonists and GPR35 antagonists to develop such ligands.

描述（由申请人提供）：许多参与疼痛和成瘾的G蛋白偶联受体在药理学和生物化学上都具有很好的特征，但是某些孤儿受体（例如GPR35和GPR55）与已知的滥用药物的受体同源，但仍然较差。 GPR55成为炎症性疼痛，神经性疼痛和骨骼发育的重要靶标，而其他研究表明GPR55激活是促癌的。 GPR55确实识别某些大麻素配体，因此被认为是第三个大麻素受体。 GPR35是疼痛（脊髓抗伤害感受和炎症性疼痛），心脏病，哮喘，代谢疾病，炎症性肠病和癌症的重要目标。仅这些领域都在医学上都是重要的，并且每个领域都会通过使用选择性激动剂和拮抗剂来进一​​步研究各自动物模型的研究。 但是，迄今为止，没有发现针对这些受体的低纳摩尔效力配体，也没有开发出用于表征结合的放射线。缺乏这种配体是该领域进步的关键障碍。该提案的目的是利用基于结构的设计和化学形象工具为GPR55激动剂和GPR35拮抗剂的重新有希望的高吞吐量，高含量筛选结果，以开发SAR为选定的脚手架开发SAR，从而导致低纳米摩尔配体保持高受体选择性。我们旨在通过基于结构的设计，分子建模，化学信息学，高通量筛选和位点定向诱变的组合来发现纳摩尔效能GPR55和GPR35配体。 公共卫生相关性：许多参与疼痛和成瘾的G蛋白偶联受体在药理学和生物化学上都具有很好的特征，但是一些孤儿受体（如GPR35和GPR55）以及与已知受体的滥用药物同源的受体同源性，仍然较差。 GPR55和GPR35都作为炎症性疼痛，癌症和代谢疾病的重要目标出现。但是，这些受体缺乏强大的激动剂和拮抗剂是进步这一领域的关键障碍。该提案的果阿是利用我们最近有望为GPR55激动剂和GPR35拮抗剂开发这种配体的高吞吐量筛选结果。