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.

目的是隔离所有神经蛋白质的主动原理 Saururus cernuus，确定其结构并评估他们为神经摄影的概况。因此，从主动分离出提取物的比例为12个新原木成分。其中，主要的活跃原则被命名为Manassantin A （MNS，安心的赐予者），而Manassantin B则少有效。除12个木质素分量之一以外的所有结构确定。 Manassantins A和B是小说的Dineolignan班。初步评估表明 MNS的表现为神经疗法：阻塞的苯丙胺刻板印象，苯丙胺和聚集诱导的毒性，条件避免回应；产生的体温过低，并释放催乳素。但是，它没有显示出毒或ptosis。互动只有多巴胺（DA）受体弱（IC 50 10-5m），DIC 不影响DA刺激的腺苷酸环化酶。因此，这些属性表明MNS确实具有神经摄影活性，但它是一种非典型的神经疗法。由于非典型神经疗法是备受追捧的药物，因为MNS 与任何其他已知的神经疗法不同的结构（非基础）并且没有氮），需要进行更详细的研究。一属性是一个相对较低的LD50，是MN的缺点，如果是永远被视为治疗剂。因此，为此赠款提出了以下特定目标： 1。根据常用参数，例如：（a）封锁各种阿氨基氨基氨基诱导的行为症状，（b）与不仅是DA的受体，而且还具有alpha 1，alpha 2肾上腺素，血清能，胆碱能（甚至是阿片类）类型，（c）研究 MNS对DA合成，释放和周转的影响。 2。通过（a）提供MNS的代谢处置重要的药代动力学参数，（b）研究组织分布和（c）隔离和评估代谢物。 3。产生一些保留非典型的特定类似物神经摄影的特征，但具有更好的治疗指数。这努力包括MN的合成及其紧密的结构和立体化学类似物；前药类型，例如酯，氧化和还原产品；基于代谢物的软药物类型方法和具有特定脑部传递能力的类似物。所有这些目标都期望不仅提供数据评估MNS（或其类似物）作为有用的治疗剂，但一般而言，神经化学疗法的作用方式也是新的。