Cannabinoid Receptors and Novel Antiglaucoma Drugs

描述(申请人提供)：该项目的长期目标是了解大麻类药物降低眼压的机制，并为开发具有更好的降眼压性能和没有大麻精神活性副作用的新型大麻类药物提供基础。在这项提议中要检验的中心假设是，大麻类化合物作用于外流通路多个靶点的特定大麻素受体，以发挥其降低眼压的作用。为了验证这一假设，我们计划了以下具体目标。(1)使用新近开发的高亲和力和/或亚型选择性的大麻素配体，测试大麻素配体的作用以及大麻素受体在人眼眼前段灌流流出通道中的作用。(2)定位大麻素的两个潜在靶点--小梁网和睫状肌中大麻素受体亚型的分布。(3)研究小梁细胞和睫状肌细胞大麻素受体的配体结合特性和信号转导机制。(4)探讨大麻素配体、大麻素受体和大麻素信号通路在小梁网和睫状肌细胞功能(如细胞骨架和基质金属蛋白酶)调控中的作用。分子生物学、细胞生物学和药理学方法的结合将被应用于拟议的研究。将尝试将从体外实验中获得的信息与体外器官灌流研究相关联，以了解大麻素受体的作用以及大麻素对房水流出的影响机制。通过研究大麻素降眼压作用的机制，本研究可能有助于发现更有效的抗青光眼大麻素配体。通过破译参与大麻素降眼压作用的特定眼部大麻素受体亚型，这项研究可能有助于将大麻素所需的降眼压作用与其不良的精神活性副作用分开。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the mechanisms for cannabinoids to lower intraocular pressure (IOP), and to provide a basis for developing novel cannabinoids with improved IOP-lowering properties, and devoid of psychoactive side-effects of marijuana. The central hypothesis to be tested in this proposal is that cannabinoids act on specific cannabinoid receptors in multiple targets of the outflow pathways to exert their IOP-lowering effects. To test this hypothesis, the following specific aims are planned. (1) To test the effects of cannabinoid ligands and the roles of cannabinoid receptors on outflow facility with perfused human ocular anterior segment, using recently developed high affinity and/or subtype-selective cannabinoid ligands. (2) To map the distribution of cannabinoid receptor subtypes in two potential targets of cannabinoids, trabecular meshwork and ciliary muscle. (3) To characterize ligand binding properties and signal transduction mechanisms of cannabinoid receptors in trabecular meshwork and ciliary muscle cells. (4) To determine the effects of cannabinoid ligands, the roles of cannabinoid receptors, and cannabinoid signaling pathways in regulating the cellular functions (such as cell cytoskeleton and matrix metalloproteases) of trabecular meshwork and ciliary muscle cells. A combination of molecular biology, cell biology and pharmacology approaches will be applied to the proposed research. Attempts will be made to correlate information gained from in vitro experiments with ex vivo organ perfusion studies in order to understand the roles of cannabinoid receptors and the mechanisms for the effects of cannabinoids on aqueous humor outflow. By investigating the mechanisms underlying the IOP-lowering effects of cannabinoids, this study may facilitate the discovery of more effective anti-glaucoma cannabinoid ligands. By deciphering specific ocular cannabinoid receptor subtypes that are involved in the IOP-lowering effects of cannabinoids, this study may help to separate the desired IOP-lowering effects of cannabinoids from their undesired psychoactive side-effects.