MANASSANTIN A, AN ATYPICAL NEUROLEPTIC AGENT

我们的目标是分离出所有的抗神经药活性成分 ，确定它们的结构，并对其进行评价 他们的抗精神病药档案。因此，从活跃的 从提取物中分离得到12个新木脂素类成分。 其中，主要的活性成分被命名为manassantiin A (MNS，给予心灵安宁的人)，Manassantin B较少 威力十足。12个木质组分中除一个外的所有组分的结构 已经下定决心。Manassantins A和B是第一批 新奇的Dineolignan类。初步评估显示， MNS表现为神经镇静剂：被阻断的安非他明刻板印象， 安非他明和聚集性毒性，有条件 回避反应；产生体温过低并导致释放 催乳素。然而，它没有表现出上睑下垂或上睑下垂； 仅与多巴胺(DA)受体弱结合(IC_(50)10~(-5)M) 不影响DA刺激的腺苷环化酶。因此，这些 属性表明MNS确实具有神经镇静剂活性，但 它就像是一种非典型的神经镇静剂。由于非典型 神经阻滞剂是非常受欢迎的药物，自从MNS以来 结构不同于任何其他已知的抗精神病药物(非碱性 而且不含氮)，需要进行更详细的研究。一 财产，相对较低的LD50，是MNS的一个缺点，如果它是 曾经被认为是一种治疗剂。因此， 为这笔赠款提出了以下具体目标： 1.确定MNS的作用机制 常用的参数如：(A)各种不同的堵塞 阿朴吗啡引起的行为症状，(B)结合 不仅是DA受体，还有α1，α2肾上腺素能受体， 血清酮能、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(A)提供以下信息来阐明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)分离和评估活性 代谢物。 3.生成一些特定的类似物，保留非典型的 抗精神病药物概况，但有更好的治疗指数。这 工作包括MNS的合成及其紧密的结构和 立体化学类似物；前药类型，如酯、氧化 和还原产品；基于代谢物的软性药物类型 方法，以及具有特定脑传递能力的类似物。 所有这3个目标预计不仅将为 评估MNS(或其类似物)是一种有用的治疗剂，但 此外，在抗精神病药物的作用模式方面也有新的线索。

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.