CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS

致幻剂的化学/行为研究

• 批准号: 6175031
• 负责人: RICHARD A GLENNON
• 金额: $ 26.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-15 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175031
• 关键词: caffeine; central nervous system stimulants; chemical structure function; chemical synthesis; dextroamphetamine; dietary supplements; discrimination learning; ephedrine; hallucinogens; isoquinolines; laboratory rat; medicinal plants; methamphetamine; nutrition related tag; phenylalkylamine; psychopharmacology; radiotracer; serotonin inhibitor; serotonin receptor; single photon emission computed tomography; substance abuse related behavior; tryptamines

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.

这项工作的长期目标是对苯烷基胺（PAA）和吲哚烷基胺（IAA）滥用药物的作用进行分类，阐明它们的结构-活性关系，并确定（在适用的情况下）它们的作用机制，这些信息应有助于更好地了解药物滥用并改进治疗方式。PAA可以产生三种不同的刺激效应，其被分类为安非他明（AMPH）样、致幻剂（或Dom）样和PMMA样（PMMA =对甲氧基甲基安非他明）。根据分子中各种取代基的存在，PAA可以产生这些效应中的任何一种或组合。 一系列的研究，调查这三种类型的活动和/或不同的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-HT 2 - 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PAA 5-HT 2拮抗剂的第一个例子。大多数研究集中在PAA设计药物的研究，“草药膳食补充剂”（例如草药迷魂药），其主要成分是苯丙醇胺麻黄碱（即，β-羟基-甲基苯丙胺）和咖啡因及其组分。 药物辨别研究建议使用大鼠训练区分PAA兴奋剂（加）AMPH，PAA致幻剂DOM，PAA设计药物MDMA和PMMA，以及苯丙醇胺麻黄碱。 初步研究结果表明：（a）MDMA（摇头丸）的作用涉及5-HT 1A成分，这可能解释了它在“糖果翻转”中的用途，（B）咖啡因增强了麻黄碱的刺激作用，并可能对其他PAA产生类似的影响，（c）AMPH训练的动物和麻黄碱训练的动物获得的刺激泛化特征之间存在相似性，但前者，而不是后者，承认甲基苯丙胺，（d）PMMA可能代表设计药物的MDMA家族的母体成员，（e）存在不同的PMMA样结构-活性关系，（f）可能将PMMA样效应与MDMA样效应分开，（g）某些以前无法分类的精神活性药物具有PMMA样作用，及（h）临时机场管理局的分类制度应解释国际机场管理局的行动。 建议通过合成（必要时）和评估适当的代理人来进一步研究这些概念。