Allosteric Modulators of CB1 Cannabinoid Receptor

CB1 大麻素受体的变构调节剂

• 批准号: 7712406
• 负责人: Ganesh A Thakur
• 金额: $ 19.5万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712406
• 关键词: Adverse effects; Affinity; Agonist; Allosteric Site; Anxiety Disorders; Binding; Biological Assay; Biological Availability; Brain; CNR1 gene; Cardiovascular Diseases; Clinical Trials; Development; Disease; Dose; Dropout; Endocannabinoids; Europe; Evaluation; Event; Exhibits; Future; G-Protein-Coupled Receptors; Goals; Health; Human; Huntington Disease; Incidence; Inflammation; Intravenous; Lead; Letters; Ligands; Malignant Neoplasms; Medical; Membrane; Mental disorders; Moods; Multiple Sclerosis; Mus; Nausea; Obesity; Oral; Osteoporosis; Pain; Pain Disorder; Parents; Parkinson Disease; Pharmaceutical Preparations; Plants; Plasma; Process; Property; Receptor Cell; Receptor Signaling; Research; SR 141716A; Series; Site; Structure; Testing; Therapeutic; Therapeutic Uses; Variant; Wood material; Work; base; cannabinoid receptor; design; drug candidate; high throughput screening; improved; in vivo; interest; liquid chromatography mass spectrometry; member; nicotine abuse; nonhuman primate; novel; public health relevance; research study; rimonabant; smoking cessation

DESCRIPTION (provided by applicant): Selective CB1 cannabinoid receptor ligands have therapeutic potential for various medical conditions, including obesity, substance (e.g. nicotine) abuse disorders, pain, inflammation, cancer, and cardiometabolic diseases. Currently, there is considerable interest in the therapeutic use of CB1 antagonists resulting from the recent approval in Europe of rimonabant (AcompliaTM, SR141716A), a CB1 antagonist. Rimonabant has also demonstrated efficacy in smoking-cessation therapy. While generally well tolerated, there was nonetheless a high dropout rate and an increased incidence of nausea and psychiatric disorders associated with rimonabant clinical trials, highlighting the need to develop safer alternatives. Developing a CB1 antagonist with a different pharmacological mechanism may represent a safer alternative. A promising alternative approach is the development of negative allosteric modulators of CB1 receptors which, by binding to a sub-type-specific and topographically distinct site from the orthosteric pocket, would inhibit the action of endocannabinoids and thus act more selectively to tune CB signaling in a site- and event-specific fashion. This approach has the potential to identify highly-selective compounds with a minimal propensity to produce adverse effects. Recently, high throughput screening from different research groups has identified two classes of ligands exhibiting allosteric antagonism at the CB1 receptor. Significant structural similarity was observed among these hits. The primary goal of this project is to develop high affinity, potent and efficacious allosteric modulators of the CB1 receptor, based on the structure of the current lead PSNCBAM-1, which will be devoid of adverse side effects. The proposed structural variations are aimed at improving affinity, potency, and physicochemical properties of the parent lead. Newly synthesized allosteric modulators will be evaluated for their ability to modulate the binding of the orthosteric ligands [3H]CP55,940 and [3H]SR141716A. A select group of novel compounds exhibiting promising results will be evaluated in a [35S]GTP3S binding assay to define their functional potency. 'Successful ligands' will be evaluated in mouse for their in vivo blood plasma and brain concentrations (BBB penetrability) following intravenous dosing utilizing quantitative LC/MS analysis. We expect that our effort will lead to the identification of "potential drug candidates" which will be evaluated subsequently in non-human primates. PUBLIC HEALTH RELEVANCE: Endocannabinoids regulate many processes in health and disease by acting through cell receptors. Modulators of endocannabinoid activity hold therapeutic promise for a wide range of medical problems, including mood and anxiety disorders, Parkinson's and Huntington's diseases, pain, multiple sclerosis, cancer, cardiovascular disease, obesity, and osteoporosis. Molecules that modify the action of cannabinoid receptors offer a new, potentially very safe approach for drugs to treat these and other diseases.

描述（由申请人提供）：选择性CB1大麻素受体配体具有各种医疗状况的治疗潜力，包括肥胖症，物质（例如尼古丁）滥用障碍，疼痛，炎症，炎症，癌症和心脏代谢疾病。当前，由于最近在欧洲批准Rimonabant（ACOMPLIATM，SR141716A）（CB1拮抗剂）批准的CB1拮抗剂的治疗使用中，引起了人们的兴趣。 Rimonabant还表现出在吸烟疗法中的功效。尽管耐受性良好，但仍然存在高辍学率，并且与利莫纳班临床试验相关的恶心和精神疾病的发生率增加，这强调了开发更安全的替代方案的必要性。开发具有不同药理机制的CB1拮抗剂可能代表更安全的选择。一种有希望的替代方法是开发CB1受体的负变构调节剂，通过与角型特异性和地形上不同的位点结合，它们将抑制内源性大麻素的作用，从而在现场和事件特异性时尚中更有选择地调整CB信号。这种方法具有鉴定具有最小倾向的高度选择性化合物，从而产生不良反应。最近，来自不同研究组的高吞吐量筛选已经确定了两类在CB1受体上表现出变构拮抗作用的配体。在这些命中中观察到了显着的结构相似性。该项目的主要目标是基于当前铅PSNCBAM-1的结构，开发CB1受体的高亲和力，有效和有效的变构调节剂，这将没有不利的副作用。所提出的结构变化旨在提高父铅的亲和力，效力和物理化学特性。将评估新合成的变构调节剂，以调节其调节正常配体[3H] CP55,940和[3H] SR141716A的结合的能力。在[35S] GTP3的结合测定中，将评估一组表现出有希望结果的新型化合物，以定义其功能效力。在小鼠中，将在小鼠中评估“成功的配体”的体内血浆和脑浓度（BBB渗透性），利用定量LC/MS分析进行静脉注射后。我们预计我们的努力将导致对“潜在候选药物”的识别，这些毒品随后将在非人类灵长类动物中进行评估。公共卫生相关性：内源性大麻素通过通过细胞受体作用来调节健康和疾病的许多过程。内源性大麻素活性的调节剂对各种医学问题，包括情绪和焦虑症，帕金森氏症和亨廷顿疾病，疼痛，多发性硬化症，癌症，心血管疾病，肥胖和骨质疏松症具有治疗性有望。改变大麻素受体作用的分子为治疗这些疾病和其他疾病的药物提供了一种新的，潜在的非常安全的方法。