Trafficking in Human CB1 Cannabinoid Receptor Signaling

人 CB1 大麻素受体信号贩运

• 批准号: 6964786
• 负责人: EVA V VARGA
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6964786
• 关键词: G protein; affinity chromatography; anesthetics; cannabinoid receptor; cannabinoids; conformation; drug adverse effect; drug design /synthesis /production; protein purification; protein structure; protein structure function; receptor binding; spectrometry; stimulant /agonist

DESCRIPTION (provided by applicant): Cannabinoid agonists, such as delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive component of marijuana, have been demonstrated to relieve pain, and to reduce chemotherapy-induced nausea and weight loss. Unfortunately, cannabinoid drugs also exhibit disturbing psychotomimetic side effects. Our goal is to develop cannabinoid Pharmaceuticals that retain the medically important pharmacological effects of delta9-THC, but produce fewer side effects. In the present proposal we plan to utilize a novel, highly sensitive experimental method, plasmon-waveguide resonance (PWR) spectroscopy to determine: a. whether structurally different classes of cannabinoid agonists stabilize unique cannabinoid receptor conformations; and, b. whether agonist-bound CB1 cannabinoid receptor conformations exhibit specificity for G protein alpha-subunits; and/or, c. G protein beta-gamma-subunits. We have already demonstrated that the PWR technique is a valuable tool to investigate agonist-mediated structural changes in G protein-coupled receptors, to measure the affinity of G protein types to the agonist-bound receptor conformations and to assess the ability of agonist-bound GPCRs to activate individual G protein types. Identification of cannabinoid drugs that exhibit selectivity for individual G protein types may provide the means to separate the medically useful effects of cannabinoids from their undesirable side effects.

描述（由申请人提供）：大麻素激动剂，如delta9-四氢大麻酚（delta9-THC），大麻的主要精神活性成分，已被证明可以缓解疼痛，减少化疗引起的恶心和体重减轻。不幸的是，大麻素类药物也表现出令人不安的拟精神副作用。我们的目标是开发大麻素药物，保留德尔塔9-四氢大麻酚的医学重要药理作用，但产生更少的副作用。在本提案中，我们计划利用一种新颖的，高灵敏度的实验方法，等离子体波导共振（PWR）光谱来确定：a.结构上不同类别的大麻素激动剂是否稳定独特的大麻素受体构象；b.激动剂结合的CB1大麻素受体构象是否对G蛋白α亚基具有特异性；和/或c. G蛋白β - γ亚基。我们已经证明，PWR技术是一种有价值的工具，可用于研究激动剂介导的G蛋白偶联受体的结构变化，测量G蛋白类型与激动剂结合受体构象的亲和力，以及评估激动剂结合的gpcr激活单个G蛋白类型的能力。鉴定对单个G蛋白类型表现出选择性的大麻素药物可能提供将大麻素的医学有用效果与其不良副作用分开的手段。