Potential anti-relapse drugs: a plant genomics approach

描述（由申请人提供）：阿坎酸、美金刚和美加明在酒精依赖中的作用表明谷氨酸受体（特别是NMDAR和mGluRS）和乙酰胆碱受体（特别是nicAChR）是预防复发的潜在分子靶点。许多来自植物的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产生具有这些分子作用的化合物的“天然产物提取物库”。该过程首先是创建大量的植物微培养物，其中已经产生了“功能获得”突变。 每种培养物都是表现出一种或多种基因过表达的代谢结果的克隆。然后在高通量药理学筛选（HTPS）中测试来自每种培养物的提取物与啮齿动物脑膜中的NMDAR和/或nicAChR蛋白的相互作用。继续产生含有“过量”受体结合活性的提取物的“子”培养物被认为是阳性的，并且这些克隆是第1阶段的可交付物。在第2阶段，将通过GC/MS分析活性提取物，以鉴定其中可能过量存在“新型”活性化合物的提取物。将对这些提取物进行功能评估，然后在与复发相关的细胞和动物模型中进行测试。在第三阶段，潜在产品将与一个专门从事药用天然产品的合作伙伴一起商业化。

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.