CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS

这项工作的长期目标是对苯烷基胺(PAA)和吲哚乙基胺(IAA)类药物的滥用行为进行分类，阐明它们的构效关系，并(在适用情况下)确定它们的作用机制，因为这些信息应有助于更好地了解药物滥用并改进治疗方式。PAAS可以产生三种不同的刺激效应，被归类为苯丙胺(AMPH)样、迷幻剂(或DOM)样和PMMA样(PMMA=对甲氧基甲基苯丙胺)。根据分子中各种取代基的存在，PAAS可以产生这些效应中的任何一种或其组合。描述了一系列研究，调查这三种类型的活动中的每一种和/或不同活动之间的相互关系。例如，我们建议开发一种放射性配体，可用于涉及5-HT2-5-羟色胺受体的SPECT成像研究--目前公认的致幻剂的作用部位。另一项研究描述了第一例PAA 5-HT2拮抗剂的研究。大多数研究集中在PAA设计药物、主要成分为苯丙醇胺麻黄碱(即β-羟甲基苯丙胺)和咖啡因及其成分的草药膳食补充剂(例如草药迷幻药)的研究上。建议使用经过训练的大鼠区分PAA兴奋剂(加)AMPH、PAA致幻剂DOM、PAA设计药物MDMA和PMMA以及苯丙醇胺麻黄素进行药物识别研究。初步发现表明：(A)设计药物MDMA(摇头丸)的作用涉及一个5-HT1a成分，这可能解释了它在“翻糖”中的用途；(B)咖啡因增强了麻黄碱的刺激效应，并可能对其他PAAs具有类似的影响；(C)在接受AMPH训练的动物和接受麻黄素训练的动物获得的刺激概括曲线之间存在相似之处，但前者而不是后者识别甲基苯丙胺；(D)PMMA可能代表MDMA家族的亲代成员，(E)存在不同的PMMA样结构-活性关系，(F)有可能区分PMMA类效应和MDMA类效应；(G)某些以前未被归类的精神活性物质具有PMMA类作用；以及(H)PAA分类方案应解释IAA的作用。建议通过合成(必要时)和评估适当的试剂来进一步研究这些概念中的每一个。

The long-term goals of this work are to classify the actions of phenyalkylamine (PAA) and indolealkylamine (IAA) drugs of abuse, to elucidate their structure-activity relationships, and to identify (where applicable) their mechanisms of action, in as much as such information should contribute to a greater understanding of drug abuse and result in improved treatment modalities. PAAs can produce three distinct stimulus effects that are classified as amphetamine-(AMPH)-like, hallucinogen-(or Dom-) like, and as PMMA-like (PMMA = p-methoxymethamphetamine). Depending upon the presence of various substituent groups in the molecules, PAAs can produce any one or a combination of these effects. A series of studies is described that investigates each of these three types of activities and/or the inter-relationships between the different activities. For example, we propose to develop a radioligand that can be used for SPECT imaging studies involving 5-HT2 serotonin receptors- the currently accepted site of action of hallucinogenic agents. Another study describes investigations with the first example of a PAA 5-HT2 antagonist. The majority of the studies center about investigations of PAA designer drugs, "herbal dietary supplements" (e.g.Herbal Ecstacy) whose major constituents are the phenylpropanolamine ephedrine (i.e., beta-hydroxy-methamphetamine) and caffeine, and their components. Drug discrimination studies are proposed using rats trained to discriminate either the PAA stimulant (plus) AMPH, the PAA hallucinogen DOM, the PAA designer drugs MDMA and PMMA, and the phenylpropanolamine ephedrine. Preliminary findings suggest (a) that the actions of the designer drug MDMA (Ecstasy) involve a 5-HT1A component that might explain its use in "candy flipping", (b) that caffeine enhances the stimulus effects of ephedrine and might have similar effects on other PAAs, (c) that similarities exist between stimulus generalization profiles obtained with AMPH-trained and ephedrine-trained animals, but that the former, not the latter, recognize methamphet-amine, (d) that PMMA may represent the parent member of the MDMA-family of designer drugs, (e) that distinct PMMA-like structure-activity relationships exist, (f) that it might be possible to separate PMMA-like effects from MDMA-like effects, (g) that certain psychoactive agents previously defying classification possess PMMA-like actions, and (h) that the PAA classification scheme should explain the actions of IAAs. It is proposed to further investigate each of these concepts by synthesizing (where necessary) and evaluating the appropriate agents.