A Novel Pharmacotherapy for Glaucoma

青光眼的新型药物疗法

• 批准号: 8767817
• 负责人: Ganesh A Thakur
• 金额: $ 51.69万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767817
• 关键词: 2-arachidonylglycerol; Adverse effects; Affect; Affinity; Age; Agonist; Animal Model; Axotomy; Binding; Biochemical; Biological Assay; Biological Availability; Blindness; CNR1 gene; Cannabinoids; Cells; Cyclic AMP; Data; Development; Dissociation; Drug Kinetics; Endocannabinoids; Evaluation; Exhibits; Eye; Fright; Future; Glaucoma; Goals; Hippocampus (Brain); Housing; Hybrids; Impairment; In Vitro; Intervention; Investigation; Knockout Mice; Lead; Ligands; Mediating; Medical; Microspheres; Modeling; Mus; Nerve Degeneration; Neurons; Ocular Hypertension; Optic Nerve Injuries; Penetration; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Physiologic Intraocular Pressure; Population; Prevalence; Preventive; Property; Receptor Activation; Receptor Signaling; Research Personnel; Retinal Ganglion Cells; Risk; Risk Factors; Role; Series; Signal Transduction; Site; Solubility; Structure-Activity Relationship; System; Testing; Therapeutic Intervention; Topical application; Vas deferens structure; Vision; Visual impairment; addiction; analog; anandamide; base; desensitization; design; disability; drug candidate; drug discovery; improved; in vivo; innovation; mouse model; neuroprotection; normotensive; novel; optic nerve disorder; patch clamp; pre-clinical; presynaptic; public health relevance; receptor; research study; scaffold; small molecule

DESCRIPTION (provided by applicant): The broad and long-term objective of this project is to develop novel CB1 cannabinoid receptor positive allosteric modulators (PAMs) and validate their utility as a safe and effective pharmacotherapy for the treatment of glaucoma. Glaucoma is a multifactorial optic neuropathy with increased intraocular pressure (IOP) as a prominent risk factor and represents an unmet medical need. It is a leading cause of vision impairment and blindness, afflicting more than 60 million people worldwide and increasing in prevalence as population age. Though diverse therapeutic interventions are available, newer and better tolerated treatments for glaucoma are desirable. Orthosteric agonists of the CB1 cannabinoid receptor significantly reduce IOP clinically and experimentally and also impart neuroprotection. However, their development has been complicated by the need to avoid psychotropic side effects and abuse liability. Very recently, a new class of ligands has been identified for CB1 cannabinoid receptors -PAMs. These compounds enhance CB1 receptor activation at a secondary site by increasing the CB1 affinity of direct agonists and /or the ability of such agonists to induce CB1 receptor signaling. Because they are expected to affect the functioning of CB1 receptors that are already being activated endogenously, PAMs should avoid some of the risks of global ocular CB1 receptor activation, including off-target activation and desensitization that come with the use of an orthosteric agonist. PAMs have been the subject of intense study for several receptor classes but are only now coming to light for CB1. We provide here preliminary evidence that a topically applied CB1 PAM reduces IOP but does not have the abuse-liability associated with CB1 agonists. In this application, we propose to develop novel small molecule CB1 PAMs based on a 2-phenylindole scaffold. Through the synthesis and biochemical evaluations of about ~50 compounds/year over a period of 5 years, we anticipate (1) discovering CB1 PAMs with biochemical and electrophysiological EC50 values of < 50 nM, excellent solubility, and good eye penetration properties; (2) evaluating them as IOP reducers in a normotensive and hypertensive mouse models with CB1 knockout mice as controls and (3) evaluating them for promoting CB1-mediated retinal ganglion cells (RGC) neuroprotective potential in: (a) ocular hypertensive mouse models (microbead and Nee) and (b) an IOP-independent model of RGC loss after optic nerve injury (axotomy). Successful completion of the proposed drug discovery investigation by an interdisciplinary team of investigators will lead to the development of potent and efficacious CB1 PAMs and establish their role as an effective pharmacotherapy for glaucoma providing both decrease in IOP and neuroprotection to RGC.

描述（由申请人提供）：该项目的广泛和长期目标是开发新型 CB1 大麻素受体正变构调节剂（PAM）并验证其作为治疗青光眼的安全有效的药物疗法的实用性。青光眼是一种多因素视神经病变，眼压（IOP）升高是一个突出的危险因素，代表着未得到满足的医疗需求。它是视力障碍和失明的主要原因，全世界有超过 6000 万人受其困扰，并且随着人口老龄化，患病率不断增加。尽管可以采用多种治疗干预措施，但仍需要更新且耐受性更好的青光眼治疗方法。 CB1 大麻素受体的正位激动剂在临床和实验上可显着降低眼压，并具有神经保护作用。然而，由于需要避免精神药物副作用和滥用倾向，它们的发展变得复杂。最近，一类新的 CB1 大麻素受体配体 -PAM 被鉴定出来。这些化合物通过增加直接激动剂的CB1亲和力和/或此类激动剂诱导CB1受体信号转导的能力来增强次级位点的CB1受体激活。由于 PAM 预计会影响已经内源性激活的 CB1 受体的功能，因此 PAM 应避免眼部 CB1 受体整体激活的一些风险，包括使用正位激动剂带来的脱靶激活和脱敏。 PAM 一直是多种受体类别的深入研究的主题，但 CB1 的研究现在才被发现。我们在此提供初步证据，表明局部应用 CB1 PAM 可以降低 IOP，但不具有与 CB1 激动剂相关的滥用倾向。在此应用中，我们建议开发基于 2-苯基吲哚支架的新型小分子 CB1 PAM。通过历时 5 年每年约 50 种化合物的合成和生化评估，我们预计 (1) 发现 CB1 PAM 的生化和电生理 EC50 值 < 50 nM，具有优异的溶解度和良好的眼部渗透性能； (2) 在正常血压和高血压小鼠模型中评估它们作为 IOP 降低剂的作用，并以 CB1 敲除小鼠作为对照；(3) 评估它们在以下情况中促进 CB1 介导的视网膜神经节细胞 (RGC) 的神经保护潜力：(a) 高眼压小鼠模型（微珠和 Nee）和（b）视神经损伤（轴切术）后不依赖 IOP 的 RGC 损失模型。由跨学科研究小组成功完成拟议的药物发现研究将导致强效且有效的 CB1 PAM 的开发，并确立其作为青光眼有效药物疗法的作用，既降低眼压又对 RGC 提供神经保护。