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: 8127697
• 负责人: JOHN M. LITTLETON
• 金额: $ 17.1万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127697
• 关键词: Agonist; Alcohol withdrawal syndrome; Alcoholism; Animal Model; Biological Factors; Biotechnology; Categories; Cell Culture Techniques; Central Nervous System Diseases; Chemicals; Commercial Sectors; Coreopsis; Drug Delivery Systems; Drug Industry; Ensure; FDA approved; Genomics; Glutamates; Helianthus; Hyperactive behavior; Ilex vomitoria; Insecta; Intellectual Property; Investigation; Kentucky; Lead; Ligands; Lobelia; Marketing; Mediating; Methods; Modeling; Modification; Molecular; Molecular Target; Mutagenesis; Nerve Degeneration; Neuroprotective Agents; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plant Extracts; Plants; Population; Prevalence; Production; Property; Relapse; Sales; Screening for Neuroblastoma; Screening procedure; Small Business Technology Transfer Research; Solidago; Technology; Testing; Therapeutic; Toxic effect; Traditional Medicine; Universities; Withdrawal; acamprosate; alpha-bungarotoxin receptor; base; commercialization; conditioning; desensitization; design; drug candidate; drug discovery; drug relapse; high throughput screening; model design; mutant; neurotoxicity; novel; programs; receptor; smoking cessation

DESCRIPTION (provided by applicant): In alcoholism, relapse and neurodegeneration share a common molecular target, glutamate NM.D.A receptor (NM.D.AR) hyperactivity, which contributes to withdrawal, pathological conditioning and neurotoxicity. In consequence, inhibitory modulators of the NM.D.AR are both potential anti-relapse and neuroprotective agents. Agonists at the functionally similar alpha7-nicotinic acetylcholine receptors (nicAChRs) cause cross-desensitization of NM.D.ARs, and should therefore have similar therapeutic value. Few synthetic drugs with these specific pharmacological actions are yet available, but the presence of homologous receptors in insect CNS suggests that plants may have evolved metabolites with appropriate pharmacology as insect defenses. As part of a phase 1 STTR, we applied a differential high throughput screening approach to more than 1000 native plant species to identify those containing putative novel compounds with the required pharmacology. Candidate species have now been prioritized for further investigation including 2 with inhibitory NM.D.AR activity, 3 with alpha7-selective nicAChR agonist activity, and 3 with both types of activity. Extract fractions from representative species inhibit NM.D.A toxicity during alcohol withdrawal in a neuroblastoma screen. None of the species have been investigated for these actions before, and chemical analysis suggests that activity resides in compounds not previously known. This phase 2 STTR aims to (a) begin genomic optimization of active plant species using proprietary technology (b) separate relatively pure active compounds, and tentatively identify these (c) test semi-purified active compounds rigorously in screens and models relevant to relapse and neurodegeneration. In phase 3, the aim is to commercialize genomically-optimized plant species, and the best drug, or lead compound candidates in partnership with a strategic partner, Yaupon Pharmaceuticals. This project combines Naprogenix Incs novel plant biotechnology methods with the chemical analytical expertise and screening methods developed at the University of Kentucky. Because active compounds may be useful in many neurodegenerative conditions, their potential commercial value extends far beyond alcoholism. Support for this phase 2 STTR will ensure that this use will be investigated first.

描述(申请人提供)：在酒精中毒中，复发和神经退行性变共享一个共同的分子靶点，谷氨酸NM.D.A受体(NM.D.AR)过度活动，导致戒断、病理条件反射和神经毒性。因此，NM.D.AR的抑制调节剂既是潜在的抗复发药物，也是神经保护剂。功能相似的α7-烟碱型乙酰胆碱受体激动剂可引起NM.D.ARs的交叉脱敏，因此应具有类似的治疗价值。具有这些特定药理作用的合成药物还很少，但昆虫中枢神经系统中同源受体的存在表明，植物可能进化出了具有适当药理作用的代谢物作为昆虫防御。作为第一阶段STTR的一部分，我们对1000多种本地植物应用了差异高通量筛选方法，以鉴定那些含有所需药理学假定的新化合物的植物。候选物种现在已被优先进行进一步研究，包括2个具有抑制NM.D.AR活性的物种，3个具有α7选择性NicAChR激动剂活性的物种，以及3个同时具有这两种活性的物种。在神经母细胞瘤筛查中，从代表物种中提取的部分抑制酒精戒断期间的NM.D.A毒性。这些物种以前都没有被研究过这些作用，化学分析表明，活性存在于以前不知道的化合物中。第二阶段STTR的目标是：(A)使用专利技术开始活性植物物种的基因组优化；(B)分离相对纯净的活性化合物，并初步鉴定这些活性化合物；(C)在与复发和神经退化相关的筛查和模型中严格测试半纯化活性化合物。在第三阶段，目标是与战略合作伙伴Yaupon制药公司合作，将经过基因优化的植物物种和最好的药物或领先候选化合物商业化。该项目将Naprogenix Incs新的植物生物技术方法与肯塔基大学开发的化学分析专业知识和筛选方法相结合。由于活性化合物可能在许多神经退行性疾病中有用，它们潜在的商业价值远远超出了酒精中毒的范畴。对此阶段2 STTR的支持将确保首先调查此使用情况。