Allosteric Modulators of CB1 Cannabinoid Receptor

CB1 大麻素受体的变构调节剂

• 批准号: 7894967
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894967
• 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治疗各种医疗状况的潜力，包括肥胖、物质（例如尼古丁）滥用障碍、疼痛、炎症、癌症和心脏代谢疾病。目前，由于CB1拮抗剂利莫那班（AcompliaTM，SR141716A）最近在欧洲获得批准，人们对CB1拮抗剂的治疗用途产生了相当大的兴趣。利莫那班在戒烟治疗中也被证明有效。尽管普遍耐受性良好，但与利莫那班临床试验相关的辍学率很高，恶心和精神疾病的发生率也有所增加，这凸显了开发更安全替代品的必要性。开发具有不同药理机制的 CB1 拮抗剂可能是一种更安全的替代方案。一种有前途的替代方法是开发 CB1 受体的负变构调节剂，该调节剂通过与正位袋中的亚型特异性和拓扑不同的位点结合，将抑制内源性大麻素的作用，从而更有选择性地调节 CB 信号传导特定于地点和事件的时尚。这种方法有可能识别出产生不良影响可能性最小的高度选择性化合物。最近，不同研究小组的高通量筛选发现了两类对 CB1 受体表现出变构拮抗作用的配体。在这些命中之间观察到显着的结构相似性。该项目的主要目标是基于当前先导PSNCBAM-1的结构，开发高亲和力、强效且有效的CB1受体变构调节剂，并且不会产生不良副作用。所提出的结构变化旨在提高母体先导化合物的亲和力、效力和理化性质。将评估新合成的变构调节剂调节正构配体[3H]CP55,940和[3H]SR141716A结合的能力。将在 [35S]GTP3S 结合测定中评估一组表现出有希望结果的新型化合物，以确定其功能效力。 “成功的配体”将在静脉给药后利用定量 LC/MS 分析在小鼠体内评估其体内血浆和脑浓度（BBB 渗透性）。我们期望我们的努力将导致“潜在候选药物”的鉴定，随后将在非人类灵长类动物中进行评估。公共卫生相关性：内源性大麻素通过细胞受体发挥作用，调节健康和疾病的许多过程。内源性大麻素活性调节剂有望治疗多种医学问题，包括情绪和焦虑症、帕金森病和亨廷顿病、疼痛、多发性硬化症、癌症、心血管疾病、肥胖和骨质疏松症。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可能非常安全的新方法。

项目成果

Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target.

利用变构改善 G 蛋白偶联受体 (GPCR) 导向的治疗：大麻素受体 1 作为发现目标。

• 发表时间: 2016-12
• 作者: Janero, David R;Thakur, Ganesh A
• 通讯作者: Thakur, Ganesh A

Scalable, One-Pot, Microwave-Accelerated Tandem Synthesis of Unsymmetrical Urea Derivatives.

不对称尿素衍生物的可扩展、一锅、微波加速串联合成。

• DOI: 10.1021/acs.joc.6b02521
• 发表时间: 2017-01-20
• 期刊: The Journal of organic chemistry
• 作者: Abhijit R. Kulkarni;Sumanta Garai;G. Thakur
• 通讯作者: G. Thakur

Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model.

1 型大麻素受体的正变构调节可减轻 R6/2 小鼠模型中亨廷顿病的体征和症状。

• 发表时间: 2019
• 影响因子: 4.7
• 作者: Laprairie, Robert B;Bagher, Amina M;Rourke, Jillian L;Zrein, Adel;Cairns, Elizabeth A;Kelly, Melanie E M;Sinal, Christopher J;Kulkarni, Pushkar M;Thakur, Ganesh A;Denovan
• 通讯作者: Denovan

Microwave-assisted Expeditious and Efficient Synthesis of Cyclopentene Ring-fused Tetrahydroquinoline Derivatives Using Three-component Povarov Reaction.

利用三组分波瓦洛夫反应微波辅助快速高效合成环戊烯环稠合四氢喹啉衍生物。

• DOI: 10.1016/j.tetlet.2013.09.107
• 发表时间: 2013-11-27
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Kulkarni AR;Thakur GA
• 通讯作者: Thakur GA