A Novel Pharmacotherapy for Glaucoma

青光眼的新型药物疗法

• 批准号: 8932005
• 负责人: Ganesh A Thakur
• 金额: $ 41.45万
• 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/8932005
• 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; Health; 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; 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的CB1大麻素受体阳性变构调节剂（PAMS），并验证其效用，以作为治疗青光眼治疗的安全有效的药物治疗。青光眼是一种多因素的视神经病变，其眼内压（IOP）是一个突出的危险因素，代表了未满足的医疗需求。这是视力障碍和失明的主要原因，在全球范围内遭受了超过6000万人的痛苦，并且随着人口年龄的增长。尽管可以使用多种治疗性干预措施，但希望对青光眼的更新和更好的耐受性治疗。 CB1大麻素受体的正骨激动剂可显着降低临床和实验性的IOP，并赋予神经保护作用。但是，由于需要避免精神副作用和虐待责任，他们的发展使他们的发展变得复杂。最近，已经确定了针对CB1大麻素受体-PAM的新的配体。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受体信号传导的能力来增强次级位点的CB1受体激活。由于预计它们会影响已经被内源性激活的CB1受体的功能，因此PAM应该避免使用全球眼CB1受体激活的某些风险，包括使用焦点激动剂而带来的靶向脱靶激活和脱敏。 PAM一直是多个受体类别的激烈研究的主题，但直到现在才揭示CB1。我们在这里提供了初步证据，表明局部应用的CB1 PAM会减少IOP，但没有与CB1激动剂相关的滥用责任。在此应用中，我们建议基于2-苯基吲哚支架开发新型的小分子CB1 PAM。通过在5年的时间内，通过约50种化合物的合成和生化评估，我们预计（1）（1）发现具有生化和电生理EC50值的CB1 PAM <50 nm，出色的溶解度，良好的眼睛渗透特性； (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).跨学科的研究人员成功完成了拟议的药物发现调查，将导致有效和有效的CB1 PAM的发展，并确立其作为青光眼的有效药物疗法的作用，从而为IOP提供了降低和神经保护症。