权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MANASSANTIN A, AN ATYPICAL NEUROLEPTIC AGENT

甲纳山汀 A，一种非典型神经阻滞剂

基本信息

批准号：
3375774
负责人：
KAMARSU V RAO
金额：
$ 8.83万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-09-28 至 1992-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3375774
关键词：
amphetamines apomorphine aquatic biology chemical structure function dopamine receptor laboratory mouse laboratory rat lignans norepinephrine plant extracts stereochemistry tranquilizer tryptamines

项目摘要

The objective is to isolate all of the neuroleptic active principles of Saururus cernuus, determine their structures, and evaluate them for their neuroleptic profile. Accordingly, from the active fraction of the extract, 12 neolignoid components were isolated. Of these, the major active principle was named manassantin A (MNS, giver of peace of mind), with manassantin B being less potent. The structures of all but one of the 12 lignoid components were determined. Manassantins A and B are the first examples of the novel dineolignan class. Preliminary evaluation showed that MNS behaved as a neuroleptic: blocked amphetamine stereotypy, amphetamine and aggregation-induced toxicity, conditioned avoidance response; produced hypothermia and caused release of prolactin. However, it showed no catalepsy or ptosis; interacted only weakly (IC 50 10-5M) with dopamine (DA) receptors and did not affect DA stimulated adenylate cyclase. Thus, these properties suggested that MNS does have neuroleptic activity but that it acts as an atypical neuroleptic. Since atypical neuroleptics are much sought-after drugs and since MNS has structure different from any other known neuroleptic (nonbasic and has no nitrogen), more detailed studies are warranted. One property, a relatively low LD50, is a drawback for MNS, if it were ever to be considered as a therapeutic agent. Hence, the following specific aims are proposed for this grant: 1. Determine the mechanism of action of MNS based on the commonly used parameters such as: (a) blockage of the various apomorphine-induced behavioral symptoms, (b) binding to receptors of not only the DA but also, alpha 1, alpha 2 adrenergic, seratonergic, cholinergic (and even opiate) type and (c) study the effects of MNS on DA synthesis, release and turnover. 2. Elucidate the metabolic disposition of MNS by (a) providing important pharmacokinetic parameters, (b) studying tissue distribution and (c) isolating and evaluating the activity of metabolites. 3. Generate some specific analogues which retain the atypical neuroleptic profile but with a better therapeutic index. This effort includes synthesis of MNS and its close structural and stereochemical analogues; prodrug types such as esters, oxidation and reduction products; soft drug types based on the metabolite approach, and analogues with specific brain-delivery capability. All 3 of these objectives are expected not only to provide data to evaluate MNS (or its analogue) as a useful therapeutic agent, but also new leads on the mode of action of neuroleptics in general.

目的是分离出所有的精神抑制剂活性成分的三白草，确定其结构，并评估因为他们的神经抑制剂。因此，从积极的从提取物中分离得到12个新甘草酸类成分。其中，主要的活性成分被命名为新木脂素A (MNS，给予心灵的平静），与manassantin B是少很有力 12种木质成分中除一种外，测定了马纳桑菌素A和B是新的dineolignan类。初步评估显示， MNS表现为一种精神抑制剂：阻断安非他明刻板印象，苯丙胺和聚集诱导毒性，条件性回避反应;产生体温过低并导致催乳素然而，它没有表现出僵硬或上睑下垂; 多巴胺（DA）受体仅弱（IC 50 10- 5 M），不影响DA刺激的腺苷酸环化酶。因此这些特性表明MNS确实具有神经安定活性，它是一种非典型的精神抑制剂由于非典型精神抑制剂是非常抢手的药物，由于MNS具有结构不同于任何其他已知的神经安定药（非碱性并且没有氮），需要更详细的研究。一相对较低的LD 50是MNS的一个缺点，被认为是一种治疗剂。所以这项赠款的具体目标如下： 1.根据以下因素确定MNS的作用机制常用的参数，如：（a）堵塞的各种阿扑吗啡诱导的行为症状，（B）结合不仅是多巴胺受体，还有α 1，α 2肾上腺素能受体，血清素能，胆碱能（甚至阿片）型和（c）研究 MNS对DA合成、释放和周转的影响。 2.通过以下方式阐明MNS的代谢处置：（a）提供重要的药代动力学参数，（B）研究组织（c）分离和评估代谢物。 3.生成一些保留非典型的特定类似物抗精神病药，但治疗指数更好。这工作包括合成MNS及其紧密的结构和立体化学类似物;前药类型，如酯、氧化和还原产物;基于代谢物的软性药物类型方法，以及具有特定脑递送能力的类似物。所有这三个目标不仅要提供数据，评估MNS（或其类似物）作为有用的治疗剂，但也是一般抗精神病药作用方式的新线索。