Drug Discovery for Mental Disorders: Preclinical Studies of Peruvian Botanicals

描述(由申请人提供)：这项提案是旨在从秘鲁植物群中发现传统上用于治疗精神障碍的新药物的长期努力的一部分。{我们的主要假设是，秘鲁传统治疗师祖先用来治疗精神疾病的植物是治疗这些疾病的新疗法的来源。我们特别假设：1)有可能从这些植物中分离出生物活性成分；2)啮齿动物行为模型是筛选/验证和进一步确定这些活性研究的优先顺序的良好起点工具；3)分离的先导化合物将在更好的生物利用度和更少的次要影响方面优于从化学图书馆获得的化合物；4)获得的药理信息将有助于进一步了解秘鲁精神障碍的传统医学概念化。之前的研究使我们收集了秘鲁几个地区和地理区域使用植物治疗精神障碍的传统方法的信息。我们目前有475种植物的提取物，对应于87个不同植物科的265个物种。这些植物传统上用于以下一种或多种活动：抗精神病、抗抑郁、抗焦虑和镇静。重要的是，其中约65%的物种从未在科学文献中被描述过它们对行为调节的潜在影响。约{20%} 到目前为止，已经对这些植物提取物进行了筛选，以通过小鼠的行为测试来验证其传统医学用途。到目前为止，我们已经确定了{70}个提取物具有一种或多种潜在的精神活性({54}抗精神病药物、{40}抗焦虑药物和{17}抗抑郁药物)。{这些提取物中有9个已经运行了剂量-反应曲线。}在这份R21中，我们建议{额外运行30个剂量-反应曲线，并进行至少1个提取物的活性指导分级。我们特别感兴趣的是开发或测试新的方法来筛选和生物测定指导分离我们的提取物，以确定可能成为治疗精神障碍的候选药物或先导化合物的新药物。此外，我们的目的是通过将我们实验中获得的药理学/行为结果与报道/解释的传统用法进行比较，进一步了解秘鲁传统药物对精神障碍的概念化。一个由专业人士组成的多学科小组已被邀请参加这次R21，最终将编制R01建议书。筛选精神障碍的天然产品提取物导致了今天正在使用的治疗药物的发现，尽管发现新的药物显然是一个雄心勃勃的目标，但有许多因素支持能够成功地识别出作为治疗精神障碍的候选药物或先导化合物的新药物的可能性。这些因素包括创新的筛选方法、我们天然产品库的独特性、项目的多学科性质以及研究人员和顾问团队的专业知识。

DESCRIPTION (provided by applicant): This proposal is part of a long {range effort} directed to the discovery of new pharmaceuticals from Peruvian flora traditionally used for the treatment of mental disorders. {Our main hypothesis is that plants ancestrally used by Peruvian traditional healers for treating mental illnesses are a source of novel therapeutics for these disorders. We specifically hypothesize that: 1) it is possible to isolate bioactive principles from these plants;2) rodent behavioral models are a good start point tool for screening/validation and for further prioritization of research on those activities; 3) the isolated lead compounds will be superior to those obtained from chemical libraries in terms of better bioavailability and less secondary effects; 4) the pharmacological information obtained will help to further understand the traditional medicine conceptualization of mental disorders in Peru. Previous studies have led us} to collect information on the traditional use of plants for the treatment of mental disorders in several Peruvian localities and geographical regions. We currently have extracts from 475 plant collections corresponding to 265 species from 87 different plant families. These plants are traditionally used for one or more of the following activities: antipsychotic, antidepressant, anxiolytic and sedative. {Importantly}, about 65% of those species have never been described in the scientific literature for their potential effects on the modulation of behavior. About {20%} of these plant extracts have been screened so far to validate its traditional medical use with behavioral tests in mice. To date we have identified {70} extracts having one or more potential psychotropic activity ({54} antipsychotic, {40} anxiolytic and {17} antidepressant). {Dose-response curves have been run for 9 of these extracts.} In this R21 we are proposing to {run 30 additional dose-response curves and pursue the activity guided fractionation of at least 1 extract. We have especial interest in developing or testing} new methods for the screening and bioassay guided fractionation of our extracts, in order to identify novel agents that could be candidate drugs or lead compounds for mental disorders. Also, we aim to get further insight on the Peruvian traditional medicine conceptualization of mental disorders, by comparing the pharmacological/behavioral results obtained in our experiments with the reported/interpreted traditional use. A multidisciplinary group of {professionals, leaders in their area of expertise,} has been invited to participate in this R21, which will end up in the preparation of an R01 proposal. Screening natural product extracts for mental disorders has led to the discovery of therapeutic agents in use today, and, although discovery of a new agent is obviously an ambitious goal, there are numerous factors that support the likelihood of being able to successfully identify novel agents that are candidate drugs or lead compounds for mental disorder treatment. These factors include the innovative screening approach, the uniqueness of our natural product library, the multidisciplinary nature of the project, and the expertise of the team of investigators and consultants.