Ajulemic acid

Throughout history, cannabis has been utilized as a medicinal substance, derived from plants of the Cannabis genus. Its principal constituents are Tetrahydrocannabinol (THC) and Cannabidiol (CBD). Cannabinoids are a group of terpenophenolic compounds discovered within cannabis and also occur naturally in the nervous and immune systems of animals. In the 1980s, researchers identified two G protein-coupled receptors that exhibit specific responses to cannabinoids: the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). Cannabinoid receptors and endogenous cannabinoids are not only involved in regulating numerous physiological functions of the central and peripheral nervous systems but also play a role in regulating the physiological functions of many peripheral sites in the human body, including the endocrine system, immune system, gastrointestinal tract, cardiovascular system, and reproductive system. CB1 receptors, although primarily found in the brain, are also expressed in the spleen, lungs, thymus, heart, and blood vessels. Within the central nervous system, their expression is highest at the axons and presynaptic terminals of neurons in the amygdala, hippocampus, cortex, basal ganglia, and cerebellum. They are closely associated with GABAergic (inhibitory) and glutamatergic (excitatory) neurons, mediating the sustained release of inhibitory and excitatory neurotransmitters. CB2 receptors are most abundantly found in tissues with immune functions outside the brain (such as the spleen, tonsils, bone marrow, pancreas, peripheral blood leukocytes) and within the brain (astroglia and microglia). They play a role in regulating immune cell migration and cytokine release, and are also involved in the cardiovascular and respiratory systems, bones, gastrointestinal tract, liver, and reproductive system. Cannabinoids can be categorized into three types based on their origin: endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Endocannabinoids are chemicals produced within the human body that attach to the same receptors (CB1 and CB2) as certain plant-derived cannabinoids. These endogenous chemical substances help in maintaining equilibrium and harmony in a healthy body. The two most extensively studied endocannabinoids, anandamide and 2-AG, along with the enzymes responsible for their metabolism, constitute the endocannabinoid system. The molecular targets of anandamide and 2-AG, along with other phytocannabinoids, are not just CB1 and CB2, but also include TRPR and GPR55. A key characteristic of endocannabinoids is that their precursors are present in lipid membranes, from which they can be synthesized through one or two rapid enzymatic steps and released into the extracellular space. Phytocannabinoids are chemical substances found and extracted from the cannabis plant. The cannabis plant contains over 100 known phytocannabinoids, with the highest concentration typically found in the unfertilized flower buds of female plants. THC (Tetrahydrocannabinol) and CBD (Cannabidiol) are the most extensively studied phytocannabinoids. Currently, only one phytocannabinoid product has been approved by the U.S. FDA, which is a CBD oral solution approved for the treatment of seizures associated with rare forms of epilepsy. The term "medical marijuana," which is not FDA-approved, lacks a scientific definition but is generally understood to be a product containing phytocannabinoids from the cannabis plant, intended to alleviate the symptoms of diseases. Synthetic cannabinoids are chemical substances created in a laboratory to mimic plant cannabinoids. The United States FDA has approved three synthetic cannabinoid products that imitate the plant cannabinoid THC. Synthetic cannabinoids may be more potent than tetrahydrocannabinol (THC) extracted from cannabis. The FDA-approved synthetic THC formulations Nabilone (sold under the brand name Cesamet) and Dronabinol (sold under the brand names Marinol and Syndros) are used for the treatment of nausea and vomiting associated with cancer chemotherapy; Dronabinol is also indicated for the treatment of anorexia associated with weight loss in patients with AIDS. According to statistics from the Synapse database, there are a total of 256 drug development pipelines worldwide targeting the cannabinoid receptors (CB1 and CB2). Approximately 119 projects (46%) are at the non-research phase, while 74 pipelines (29%) are at the pre-clinical research stage. Five drugs have been approved for the market, including Cannabidiol, Dronabinol, and Rimonabant. Six drug candidates are in the clinical phase 2/3 or phase 3 study stages, and 23 are in clinical phase 2. Apart from the development of subtype-selective therapeutic drugs for CB1 or CB2, some pharmaceutical research efforts focus on developing non-selective CB1/CB2 drug molecules and multi-target drugs that act on both CB1/2 and other receptors such as 5-HT1A and NMDA receptors. Clinical indications and drug development opportunities targeting CB1 and CB2 receptors include: treatments for neurological disorders (such as neuropathic pain, epilepsy, Parkinson's disease, etc.), metabolic diseases (such as obesity, type 2 diabetes, non-alcoholic fatty liver disease, etc.), pain management (pain and neuropathy), immune system modulation (such as rheumatoid arthritis, inflammatory bowel disease, etc.), anti-cancer therapies, and interventions for substance addiction and mental health, among others. Novel therapeutics targeting CB1 and CB2 receptors may comprise agonists, antagonists, partial agonists, biased agonists, allosteric modulators, etc., to more precisely regulate the activity of the endocannabinoid system and reduce side effects. Cannabidiol/Dronabinol (CBD/THC) is a medication developed by GW Pharmaceuticals for the treatment of sleep initiation and sleep disorders, which was first approved for sale in Germany in 2022. Cannabidiol is an active cannabinoid found in cannabis, which can be extracted from cannabis or hemp plants. It is used to treat seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, as well as relief for moderate to severe neuropathic pain or other pain symptoms. While its precise medical impact is under investigation, Cannabidiol has shown promise as an analgesic, anticonvulsant, muscle relaxant, anxiolytic, antipsychotic, and it has also shown neuroprotective, anti-inflammatory, and antioxidant activities. Dronabinol is a synthetic Δ9-tetrahydrocannabinol (Δ⁹-THC) that functions through mild partial agonist activity on CB1 and CB2 receptors, producing effects known from cannabis consumption such as increased appetite, pain relief, and altered mood and cognitive processes. It has been approved in various countries and regions for treating anorexia associated with weight loss in AIDS patients, as well as for nausea and vomiting caused by chemotherapy in cancer patients who have not responded adequately to conventional antiemetic treatments. GW Pharmaceuticals has established a world-leading cannabinoid science platform for the development of a deep, innovative portfolio of early and late-stage cannabinoid product candidates, along with highly specialized cultivation and manufacturing technologies. GW was also the first to develop and commercialize the world's first prescription medicine derived from the cannabis plant. Unlike CBD products or cannabis derivatives not approved by the FDA, GW's portfolio of regulator-approved products ensures that each of them undergoes a thorough evaluation of safety and efficacy through clinical trials, independent peer reviews, regulator approvals, and is consistently produced to the highest quality standards. In 2021, JAZZ Pharmaceuticals acquired GW Pharmaceuticals for $7.2 billion. Rimonabant is an anorectic anti-obesity drug originally researched, developed, produced, and marketed by the company Sanofi-Aventis. It acts as a reverse agonist for the cannabinoid receptor CB1, with its primary mechanism of action being the reduction of appetite. Rimonabant was the first selective CB1 receptor blocker to be approved for use globally, and after its initial market approval in 2006, it received authorization in 38 countries including the European Union, Mexico, and Brazil. However, its application for market approval was rejected by the U.S. FDA due to potential risks of increased suicidal thoughts and depression. Early clinical observations noted that cannabis stimulates appetite, suggesting the involvement of the endogenous cannabinoid system in the control of energy balance. Rimonabant was the first CB1 receptor antagonist to be marketed and was developed as an anti-obesity drug intended to decrease food intake by blocking central cannabinoid activity. Around 2005-2006, Sanofi-Aventis and clinical research teams published articles in "The Lancet" (two papers) and "The New England Journal of Medicine," discussing the effects of Rimonabant on weight reduction and cardiovascular risk factors in overweight patients, the influence on metabolic risk factors in patients with overweight dyslipidemia, and the efficacy and tolerability in overweight or obese patients with type 2 diabetes. The results indicate that for overweight or obese patients with Type 2 diabetes who exhibit inadequate glycemic control with metformin or sulfonylureas, a combined treatment of 20 mg/day Rimonabant with diet and exercise can lead to weight reduction and improvement in HbA1c, as well as a range of cardiovascular and metabolic risk factors, which is clinically significant. However, a meta-analysis of all published randomized controlled trials has shown that taking 20 mg of Rimonabant daily increases the risk of psychiatric adverse events (mood disorders including depressive disorders and anxiety). Adverse events associated with Rimonabant were significantly more frequent than with placebo, with severe adverse events occurring 1.4 times more often than with placebo. Patients taking Rimonabant were 2.5 times more likely to discontinue treatment due to depressive mood disorders compared to those receiving a placebo. The U.S. FDA analyzed four major trials as well as unpublished studies and found that taking Rimonabant (20 mg/day) resulted in a higher incidence of psychiatric adverse reactions compared to placebo. Furthermore, it was reported that two patients taking Rimonabant died from suicide. The United States never approved the drug for the treatment of obesity. Subsequently, European regulatory authorities revoked the marketing authorization for Rimonabant. Taranabant is a small molecule CB receptor inverse agonist originally developed by Merck & Co. It is reported that phase 3 clinical trial data for taranabant in overweight patients showed a weight reduction effect similar to that of Rimonabant. However, due to potential side effects and other reasons, Merck & Co. terminated the clinical development of taranabant. Subsequently, numerous clinical research projects associated with CB1 antagonists were discontinued as a result of this impact, but some products continue to be developed. INV-202 is a CB1 receptor antagonist developed by Inversago Pharma. Learning from prior endeavors, Inversago Pharma's second-generation CB1 receptor antagonists are designed to reduce the permeability of the molecules through the blood-brain barrier, thereby confining the drug molecules to the peripheral system outside of the central nervous system. According to a phase 1b clinical study report updated in 2023, INV-202 showed good tolerability with no serious or severe treatment-emergent adverse events noted; the most common side effects were related to the known gastrointestinal impacts of CB1 receptor blockade. INV-202 significantly reduced average body weight by 3.5 kilograms and also notably decreased waist circumference and body mass index. In August this year, Novo Nordisk and Inversago Pharma announced that Novo Nordisk has agreed to acquire Inversago for up to $1.075 billion in cash, subject to achieving certain development and commercial milestones. Corbus Pharmaceuticals, another company dedicated to the development of drugs targeting the CB receptor system, has announced that it is working on developing a second-generation CB1 receptor antagonist, CRB-913, which is currently in the clinical declaration stage. Clinical pre-study data updated in November by the company indicate that CRB-913 has a low entry rate into the brain yet demonstrates significant weight loss effects. Ajulemic acid (Lenabasum) is another CB2 receptor agonist and IL-1β inhibitor developed by Corbus Pharmaceuticals in the United States, currently in Phase III clinical trials. Early clinical study results have indicated that Ajulemic acid can relieve pain in patients with chronic neuropathic pain without the clinically relevant psychoactive or physical side effects. Presently, this medication is being clinically investigated for a range of dermatological conditions, including discoid lupus erythematosus, dermatomyositis, systemic sclerosis, cystic fibrosis, and systemic lupus erythematosus. CardiolRx (Cannabidiol) is a CB1/CB2 inverse agonist developed by Cardiol Therapeutics. Clinical indications under investigation for this compound include cardiovascular diseases, pericarditis, myocarditis, and heart failure. CB1/CB2 Novel Drug Development StrategiesDespite the broad therapeutic potential of CB1/CB2, the development of candidate drugs is hindered by adverse reactions, rapid tolerance development, and the possibility of abuse. It has been proposed that ligands might differentiate the therapeutic effects from adverse reactions by producing biased signaling as a novel drug development strategy for the CB1/CB2 receptors. However, due to a lack of highly biased agonists, there is limited understanding of the biased signaling of the CB1 receptor. Researchers are investigating the biased signaling characteristics of classical cannabinoid agonists and isomeric ligands in search of potential therapeutic advantages of CB1 receptor biased signaling in various pathological conditions. CP55940 is a synthetic cannabinoid originally developed by Pfizer in 1974. It can mimic the effects of natural tetrahydrocannabinol, acting as an agonist for CB1/CB2 receptors. CP55940 is reported to be 45 times more potent than Δ9-THC and can be completely antagonized by Rimonabant. It is used as a research tool to study the endocannabinoid system but has never been studied clinically or sold on the market. A study published in the "Journal of Molecular Pharmacology" (DOI: 10.1124/mol.115.101980) indicates that among the several downstream signaling pathways of the CB1 receptor, agonists THC and CP55940 show a preference for signaling through β-arrestin1, whereas the endogenous cannabinoids 2-AG and AEA exhibit a preference for signaling through Gαi/o. The researchers believe that enhancing Gαi/o-based endogenous cannabinoid signaling could have therapeutic effects for Huntington's disease. In contrast, drugs that preferentially target the β-arrestin1 signaling pathway could be detrimental to therapeutic signaling downstream of the CB1 receptor, especially in patients with Huntington's disease where CB1 receptor levels are already reduced. ORG27569 is an allosteric modulator targeting the CB1 receptor. It has been reported that ORG27569 is a ligand biased towards the β-arrestin1 signaling pathway of the CB1 receptor, acting as a negative allosteric modulator in terms of G protein signaling, and as a positive allosteric modulator in the context of β-arrestin1-mediated pERK1/2 signaling. Recent research results published in the journal "Cell" (DOI: 10.1016/j.cell.2023.11.017) by Professor Zhang Yan and collaborators from Zhejiang University have filled a knowledge gap in structural biology regarding how the CB1 receptor couples to downstream β-arrestin signaling proteins.  By comparing the subtle structural differences between the inactive state bound to an antagonist, the active state with agonist-receptor-Gi protein binding, and the state with agonist-receptor-β-arrestin1 binding, the researchers seem to have found some clues about the bias of downstream CB1 receptor activation. This may provide a structural basis for designing safer analgesic and anti-anxiety medications.

关于大麻和大麻素受体历史上大麻是一种药品，由大麻属植物制成，其主要的成分为四氢大麻酚（Tetrahydrocannabinol, THC）和大麻二酚 (Cannabidiol，CBD)。大麻素是从大麻里发现的一组萜酚类化合物，也自然地存在于动物神经和免疫系统里。1980年代，人们发现了两种对大麻素有特异反应的 G 蛋白偶联受体，分别是大麻素受体 1（CB1）和大麻素受体 2（CB2）。大麻素受体和内源性大麻素不仅参与调节中枢和外周神经系统的许多生理功能，还参与调节人体许多外周部位的生理功能：内分泌系统、免疫系统、胃肠道、心血管系统和生殖系统。CB1 受体虽然主要存在于大脑，但在脾脏、肺、胸腺、心脏和血管中也有表达。在中枢神经系统中，它们在杏仁核、海马、皮层、基底节和小脑中神经元的轴突和突触前末梢的表达量最高。它们与 GABA 能（抑制性）和谷氨酸能（兴奋性）神经元密切相关，介导抑制性和兴奋性神经递质的持续释放。CB2 受体在脑外（如脾脏、扁桃体、骨髓、胰腺、外周血白细胞）和脑内（星形胶质细胞和小胶质细胞）具有免疫功能的组织中最为丰富。它们具有调节免疫细胞迁移和细胞因子释放的功能，还在心血管和呼吸系统、骨骼、胃肠道、肝脏和生殖系统中发挥作用。大麻素根据其来源可分为 3 类：内源性大麻素、植物性大麻素和合成大麻素。内源性大麻素是人体内产生的化学物质，与某些植物大麻素一样附着在相同的受体(CB1 和CB2）。内源性大麻素化学物质有助于维持健康身体的平衡与和谐。研究最为广泛的两种内源性大麻素，即 Anandamide 和 2-AG，以及负责内源性大麻素代谢的酶，构成了内源性大麻素系统。 Anandamide 和 2-AG 以及其他植物大麻素的分子靶标不仅仅是 CB1 和 CB2，还有 TRPR 和 GPR55。内源性大麻素的一个主要特点是其前体存在于脂膜中，可通过一到两个快速酶解步骤合成，并释放到细胞外空间。 植物性大麻素是从大麻植物中发现和提取的化学物质。大麻植物含有 100 多种已知的植物大麻素，通常植物大麻素在雌株未播种的花蕾中含量最高。THC 和 CBD 是研究最广泛的植物大麻素。目前只有一种植物大麻素产品获得了美国 FDA 的批准，即 CBD 口服液，该产品被批准用于治疗与罕见癫痫相关的癫痫发作。 非 FDA 批准的 "医用大麻 "没有科学定义，但一般认为它是一种含有大麻植物中植物大麻素的产品，旨在缓解疾病症状。合成大麻素是在实验室中模仿植物大麻素制成的化学物质。美国 FDA 批准了 3 种合成大麻素产品，这些产品模仿植物大麻素 THC。合成大麻素可能比大麻提取的四氢大麻酚更有效。美国 FDA 批准的合成四氢大麻酚制剂 Nabilone (大麻隆) 和  Dronabinol(屈大麻酚) 适用于治疗与癌症化疗有关的恶心和呕吐；Dronabinol还适用于治疗与艾滋病患者体重减轻有关的厌食症。大麻素受体配体从结构上可分为五大化学类：经典类、非经典类、氨基烷基吲哚类、二十烷类和类肽化合物。经典类包含二苯并呋喃衍生物，其中最著名的是Δ9-THC 和 HU-210，后者是Δ8-THC 的合成类似物。非经典类包括缺少吡喃环的Δ9-THC 双环和三环类似物，如 (-)-CP 55,940 等。氨基烷基吲哚类（以 (+)-WIN 55,212-2 为代表）和二十烷类（由内源性大麻素组成）的结构与经典和非经典大麻素受体激动剂截然不同，彼此也有区别。类肽化合物包括内源性 Hemopressin、其衍生物 RVD-Hpα 和 VD-Hpα 以及新型 Pep19 都被证明具有大麻素受体配体的功能。新药研发简报根据智慧芽新药情报库统计，全球靶向大麻素受体 ( CB1 和 CB2 ) 的药物研发管线合计 256 例，其中约 119 个 (46%) 管线处于非在研阶段，74 个 (29%) 管线处于临床前研究阶段。5 款药物已获批上市 (Cannabidiol/Dronabinol大麻二酚/四氢大麻酚 和 Rimonabant) ，6款药物处于临床2/3期或3期研究阶段，23款药物处于临床2期。除开发具有亚型选择性的 CB1 或 CB2 治疗性药物外，部分药物研发工作聚焦开发非选择性的 CB1/CB2 药物分子以及 CB1/2 与 5-HT1A、NMDA 受体等的多特异性药物。靶向 CB1 和 CB2 受体的临床适应症及药物研发机会包括：神经系统疾病治疗（如神经痛、癫痫、帕金森病等）、代谢性疾病（如肥胖、2型糖尿病、非酒精性脂肪性肝炎等）、疼痛管理（疼痛和神经痛）、免疫系统调节（如类风湿性关节炎、炎症性肠病等）、抗癌治疗和药物成瘾和心理健康等。针对 CB1 和 CB2 受体的新型药物可能包括激动剂、拮抗剂、部分激动剂、偏向性激动剂、别构调控剂等，以更精确地调节大麻素系统的活性，减少副作用。Cannabidiol/Dronabinol（大麻二酚/四氢大麻酚）是由 GW Pharmaceuticals 公司原研开发的一款治疗入睡和睡眠障碍的药物，2022 年首次在德国获批上市。Cannabidiol 是一种存在于大麻中的活性大麻素，可从大麻或非大麻植物中提取，可用于治疗与 Lennox-Gastaut 综合征或 Dravet syndrome 综合征相关的癫痫发作，以及缓解中度至重度神经性疼痛或其他疼痛症状。尽管目前正在研究其确切的医学影响，Cannabidiol 已显示出镇痛、抗惊厥、肌肉松弛、抗焦虑、抗精神病的前景，并显示出神经保护、抗炎和抗氧化活性等。Dronabinol是一种合成的 Δ9-四氢大麻酚（Δ⁹-THC），通过对 CB1 和 CB2 受体产生微弱的部分激动活性来发挥其作用，从而产生众所周知的吸食大麻的效果，如增加食欲、减轻疼痛以及改变情绪和认知过程。它已被不同国家和地区被批准用于治疗艾滋病患者因体重减轻而引起的厌食症，以及治疗因癌症化疗而引起的恶心和呕吐，这些患者对常规止吐药治疗无效。GW Pharmaceuticals 建立了世界领先的大麻素科学平台，以开发深层次、创新性的早期和晚期大麻素候选产品管线，以及高度专业化的种植和制造技术。GW 也是全球率先开发出了世界上第一种从大麻植物中提取的处方药并实现了商业化。与未经 FDA 批准的 Cannabidiol 产品或大麻衍生产品不同，GW 获得监管机构批准的产品组合可确保所生产的每一种产品的安全性和疗效都经过临床试验的全面评估、独立的同行评审、监管机构的批准，并始终如一地进行生产，以确保达到最高质量标准。2021年，JAZZ 公司耗资72亿美元将 GW Pharmaceuticals 公司收入麾下。Rimonabant 是由 Sanofi-Aventis 公司原研开发、生产和销售的一种厌食抗肥胖药物。它是大麻素受体 CB1 的反向激动剂，其主要作用途径是降低食欲。Rimonabant 是全球首个获准使用的选择性 CB1 受体阻断剂，2006 年首次获批上市后已在包括欧盟、墨西哥和巴西在内的 38 个国家获得批准。但该药在美国 FDA 的上市申请被驳回，这一决定是因为它可能会增加自杀念头和抑郁情绪。早期的临床观察发现，大麻会刺激食欲，这表明内源性大麻素系统参与了能量平衡的控制。Rimonabant 是第一种上市的 CB1 受体拮抗剂，被开发为抗肥胖药，通过阻断中枢大麻素活性可能会减少食物摄入量。2005-2006年前后，Sanofi-Aventis 及临床研究团队分别在《柳叶刀》(2篇)和《新英格兰医学杂志》撰文，介绍了Rimonabant 对超重患者减轻体重和心血管风险因素的影响、超重血脂异常患者代谢风险因素的影响以及对超重或肥胖 2 型糖尿病患者的疗效和耐受性。结果表明，对于二甲双胍或磺脲类药物控制不佳的超重或肥胖 2 型糖尿病患者来说，20 mg/天的Rimonabant 与饮食和运动相结合，可以减轻体重，改善 HbA1c 以及一系列心血管和代谢风险因素，具有临床意义。然而，对所有已发表的随机对照试验进行的一项元分析 (meta-analysis) 结果表明，每天服用 20 mg 的Rimonabant会增加精神不良事件（抑郁性情绪障碍和焦虑）的风险。Rimonabant引起的不良事件明显多于安慰剂，严重不良事件是安慰剂的 1.4 倍。服用Rimonabant的患者因抑郁情绪障碍而中断治疗的可能性是服用安慰剂患者的 2.5 倍。美国 FDA 对四项主要试验以及未发表的试验进行了分析，发现服用Rimonabant（20 mg/天）比服用安慰剂更容易出现精神方面的不良反应。此外，据报道有两名服用Rimonabant的患者死于自杀。美国从未批准该药物用于治疗肥胖症。此后，欧洲监管当局取消了Rimonabant的上市许可。Taranabant 是一款由 Merck 公司原研开发的一款 CB 受体小分子类反向激动剂。据悉，Taranabant 对超重病人的临床3期研究数据表现出与Rimonabant 相似的减重效果，但由于潜在的副作用等原因，Merck 公司终止了对 Taranabant 的临床开发。此后，多项与CB1 拮抗剂相关的临床在研项目受此影响而宣告终止，包括阿斯利康、辉瑞、BMS、AbbVie 等跨国大药企。明知前路艰险，但依然有勇士无畏前行。INV-202 是一款由 Inversago Pharma 公司开发的一款 CB1 拮抗剂。前车之鉴，Inversago Pharma 公司开发的第二代 CB1 受体拮抗剂拮抗剂旨在降低分子对血脑屏障的通透效率，将药物分子限定在中枢神经系统之外的外周系统。根据23年更新的一份临床1b期研究报告，INV-202的耐受性良好，没有出现严重或严重的治疗突发不良事件；最常见的不良事件与已知的 CB1 受体阻断对胃肠道的影响有关。INV-202 显著降低了3.5公斤的平均体重，同时还显著降低了腰围和体重指数。今年8月诺和诺德公司和 Inversago Pharma 宣布，诺和诺德已同意在达到某些开发和商业里程碑的情况下，以最高 10.75 亿美元的现金收购 Inversago。另一位长期致力于 CB 受体系统药物开发的公司 Corbus Pharmaceuticals 公司宣布，公司正在致力于开发第二代 CB1 受体拮抗剂 CRB-913，该项目目前处于临床申报阶段。根据公司11月更新的临床前研究数据表明，CRB-913 进入大脑的比例很低，而减肥效果显著。临床前的减肥数据，如此振奋人心。加之近几年肥胖市场的大热，Corbus 公司对CB1 受体相关管线的调整思路非常明显。Ajulemic acid (Lenabasum) 是由美国 Corbus Pharmaceuticals 公司原研开发的另一款 CB2 受体激动剂和 IL-1β 抑制剂，目前处于临床3期阶段。早期的临床研究结果表明，Ajulemic acid 对慢性神经病理性疼痛患者有止痛作用，但没有临床相关的精神或身体副作用。目前，该药的正在围绕盘状红斑狼疮、皮肌炎、系统性硬皮病、囊性纤维化、系统性红斑狼疮等皮肤疾病进行临床研究。(但该项目在近期的公司管线汇报中并未提及。)CardiolRx (Cannabidiol) 是一款由 Cardiol Therapeutics 公司原研开发的一款 CB1/CB2 反向激动剂。在研临床适应症为心血管疾病、心包炎、心肌炎和心脏衰竭。CB1/CB2 新药开发策略尽管 CB1/CB2 具有广泛的治疗潜力，但候选药物的开发却受到不良反应、快速耐受性发展和滥用可能性的阻碍。有人提出，配体是否可通过产生偏向性信号转导，作为一种新药开发策略，将 CB1/CB2 受体的治疗效果和不良反应区分开来。但由于缺乏强偏性激动剂，人们对 CB1 受体的偏性信号转导了解甚少。研究人员对经典大麻素激动剂和异构配体的偏向信号转导特征进行调查研究，寻找 CB1 受体偏向信号转导在不同病理状态下的潜在治疗优势。CP55940 是一款由辉瑞公司 1974 年原研开发的一种合成大麻素。它可模拟天然四氢大麻酚的效果，作为 CB1/CB2 激动剂发挥作用。据报道，CP55940 的药效是 Δ9-THC 的 45 倍，能被Rimonabant完全拮抗，被用作研究内源性大麻素系统的研究工具，但从未进行临床研究或在市场上销售。一篇发表于《分子药理学杂志》的研究 (DOI: 10.1124/mol.115.101980) 表明，在 CB1 受体下游的多条信号通路中，激动剂 THC 和 CP55940 显示出偏向于 β-arrestin1 的信号转导，而内源性大麻素 2-AG 和 AEA 显示出偏向于 Gαi/o 的信号转导。研究人员认为，加强基于 Gαi/o 的内源性大麻素信号转导可能对亨廷顿病有治疗作用。与此相反，偏向于 β-arrestin1 信号通路的药物可能对 CB1 受体下游的治疗性信号转导有害，尤其是在 CB1 受体水平已经降低的亨廷顿病患者中。ORG27569 是一款靶向 CB1 受体的别构调控剂。据报道，ORG27569 是一种偏向于 CB1 受体的 β-arrestin1 信号通路的配体，在 G 蛋白信号传导方面起着负向别构激动剂的作用，而在 β-arrestin1 介导的 pERK1/2 信号传导方面起着正向别构激动剂的作用。 一篇近期由浙江大学张岩教授及合作者发表于《细胞》(DOI: 10.1016/j.cell.2023.11.017) 杂志的研究成果，弥补了结构生物学领域对于 CB1 受体如何偶联到下游 β-arrestin 信号蛋白的知识空缺。通过对比处于拮抗剂结合的非激活态、激动剂-受体-Gi 蛋白结合的激活态和激动剂-受体-β-arrestin1 态的细微结构差异。研究人员似乎对 CB1 受体下游偏向性激动找到了一些线索，这可能为设计更安全的镇痛和抗焦虑药物提供了结构基础。以上文章来源于GPCR drug diacovery，作者段思研       本文仅作信息交流之目的，文中观点不代表相关疾病治疗立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。