Potential anti-relapse drugs: a plant genomics approach

描述（由申请人提供）：在酒精中毒中，复发和神经退行性变有一个共同的分子靶点，即谷氨酸NM.D.A受体（NM.D.AR）亢进，它有助于戒断、病理条件反射和神经毒性。因此，NM.D.AR的抑制性调节剂既是潜在的抗复发剂又是神经保护剂。功能相似的α 7-烟碱乙酰胆碱受体（nicAChRs）的激动剂可引起nmd的交叉脱敏。因此应该具有类似的治疗价值。目前很少有具有这些特异性药理作用的合成药物，但昆虫中枢神经系统中同源受体的存在表明，植物可能已经进化出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多种本地植物物种采用了差异高通量筛选方法，以鉴定那些含有假定的具有所需药理作用的新化合物。候选物种目前已被优先考虑进行进一步研究，其中2种具有抑制NM.D.AR活性，3种具有α 7选择性nicAChR激动剂活性，3种具有两种活性。在神经母细胞瘤筛选中，来自代表性物种的提取物在酒精戒断期间抑制NM.D.A毒性。在此之前，没有任何一种植物被研究过这些作用，化学分析表明，这些活性存在于以前不知道的化合物中。该二期STTR旨在(a)使用专有技术开始活性植物物种的基因组优化；(b)分离相对纯的活性化合物，并初步鉴定这些活性化合物；(c)在与复发和神经退行性变相关的筛选和模型中严格测试半纯化的活性化合物。在第三阶段，目标是与战略合作伙伴Yaupon Pharmaceuticals合作，将基因组优化的植物物种和最佳药物或主要候选化合物商业化。该项目将Naprogenix公司新颖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对许多神经退行性疾病有用，它们潜在的商业价值远远超出了酒精中毒。对第二阶段str的支持将确保首先对这种用途进行调查。

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.