Potential anti-relapse drugs: a plant genomics approach

潜在的抗复发药物：植物基因组学方法

• 批准号: 6887533
• 负责人: JOHN M. LITTLETON
• 金额: $ 10.71万
• 依托单位: NAPROGENIX, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887533
• 关键词: NMDA receptors; alcoholism /alcohol abuse chemotherapy; alcoholism antagonist; amantadine; behavioral /social science research tag; biotechnology; chemical registry /resource; drug /alcohol abstinence; drug discovery /isolation; drug interactions; drug screening /evaluation; gas chromatography mass spectrometry; glutamate receptor; high throughput technology; laboratory rat; mecamylamine; nicotinic receptors; pharmacokinetics; plant extracts; receptor binding; tissue /cell culture

DESCRIPTION (provided by applicant): The actions of acamprosate, memantine and mecamylamine in alcohol dependence suggest that glutamate receptors (specifically NMDARs and mGluRSs) and acetylcholine receptors (specifically nicAChRs) are potential molecular targets for prevention of relapse. Many natural products from plants interact with these receptors, and the specific aim of phase 1 is to generate a "natural product extract library" of compounds with these molecular actions using a plant genomics approach. The process is first to create a large population of plant microcultures in which "gain of function" mutations have been produced. Each culture is a clone exhibiting the metabolic consequences of over-expression of one or more genes. An extract from each culture is then tested in high throughput pharmacological screens (HTPS) for interactions with NMDAR and/or nicAChR proteins in rodent brain membranes. "Daughter" cultures that continue to produce extracts containing an "excess" of receptor binding activity are regarded as positive, and these clones are the deliverables for phase 1. In phase 2, active extracts will be analyzed by GC/MS to identify those in which "novel" active compounds may be present in excess. These extracts will be evaluated functionally, and then tested in cellular and animal models relevant to relapse. In phase 3, potential products will be commercialized with a partner specializing in pharmaceutical natural products.

描述（由申请人提供）：阿康戊酸、美金刚和甲胺在酒精依赖中的作用表明谷氨酸受体（特别是NMDARs和mGluRSs）和乙酰胆碱受体（特别是nicachr）是预防复发的潜在分子靶点。来自植物的许多天然产物与这些受体相互作用，第一阶段的具体目标是使用植物基因组学方法生成具有这些分子作用的化合物的“天然产物提取物文库”。这个过程首先是创造大量的植物微培养物，在这些微培养物中产生了“功能增益”突变。