CHEMICAL/BEHAVIORIAL STUDIES ON HALLUCINOGENIC AGENTS

我们工作的总体目标是阐明其作用机制 经典致幻剂和结构上相关的苯异丙胺 (PIAS)和吲哚乙基胺(IAA)。由于一系列的诉讼 然而，某些药物，这种研究要求这些药物首先 适当地归类。例如，PIA滥用药物的情况可以分为 分为三大类：致幻剂(如DOM、道布)、中央 兴奋剂(如安非他明或安非他明)和特制药物。我们有 利用毒品歧视范式，证明了某些 设计师设计的药物产生类似DOM的效果，有些产生像Amph一样的效果， 有些(如丙二醛)产生两种效果，还有一些(如PMMA)产生 都不是。我们提出了5-HT2假说来解释这些行为 PIA和IAA迷幻剂。安非他明类中枢兴奋剂可能通过 一种儿茶酚胺能机制。非DOM的作用机理-- 像/不像安非他明的设计师药物是未知的。 尽管5-HT2假说表明经典迷幻剂 5-HT2激动剂，这一点从未得到充分证明；它是 建议通过以下方法确定经典迷幻剂的疗效 检测它们对PI代谢的影响。由于一部小说的发现 5-HT2受体，5-HT2B受体，我们建议确定 它们在经典致幻剂的作用中的作用，如果有的话，通过 进行放射性配基结合研究。PMMA是一种新型的PIA设计药物 它缺乏类似DOM和AMPH的属性；我们建议调查 该试剂采用药物识别技术，以大鼠为研究对象。 此外，因为有证据表明，PIA药物的不同效果 我们认为，滥用可能与不同的侧链构象有关 合成和评价一系列构象受限的新型化合物 专门为检验这一假说而设计的试剂。最后，虽然 滥用IaaS通常被认为是致幻的，我们 提供证据表明，它们与PIA一样，也可以分为 有几个类别。例如，新设计的药物阿尔法-ET产生 中枢刺激和DOM样效应，以及非DOM样和非DOM样效应 像安眠药一样的效果。我们建议对这种新型药物进行研究。 歧视研究。因此，总而言之，我们打算进一步确认 致幻药物作用的5-HT2假说 时间，来调查几个新的和有趣的动作 与结构相关的PIA和IAA设计药物。

The overall goal- of our work is elucidation of the mechanisms of action of classical hallucinogens and structurally related phenylisopropylamines (PIAs) and indolealkylamines (IAAs). Due to a multiplicity of action for certain agents, however, such studies require that these agents first be appropriately categorized. For example, PIA drugs of abuse can be divided into three broad categories: hallucinogens (e.g. DOM, DOB), central stimulants (e.g. amphetamine or AMPH), and designer drugs. We have demonstrated, using the drug discrimination paradigm, that certain designer drugs produce DOM-like effects, some produce AMPH-like effects, some (e.g. MDA) produce both effects, and yet others (e.g. PMMA) produce neither. We have proposed the 5-HT2 hypothesis to account for the actions of PIA and IAA hallucinogens. AMPH-like central stimulants likely act via a catecholaminergic mechanism. The mechanism of action of non-DOM- like/non-AMPH-like designer drugs is unknown. Although the 5-HT2 hypothesis suggests that classical hallucinogens are 5-HT2 agonists, this has never been adequately demonstrated; it is proposed to determine the efficacy of classical hallucinogens by examining their effect on PI metabolism. Due to the discovery of a novel population of 5-HT2 receptors, 5-HT2B receptors, we propose to determine their role, if any, in the action of classical hallucinogens by conducting radioligand binding studies. PMMA is a new PIA designer drug that lacks DOM-like and AMPH-like properties; we propose to investigate this agent using drug discrimination techniques with rats as subjects. Also, because evidence suggests that the different effects of PIA drugs of abuse may be related to different side-chain conformations, we propose to synthesize and evaluate a series of novel conformationally-restricted agents specifically designed to test this hypothesis. Finally, although IAAs of abuse are typically considered only as being hallucinogenic, we provide evidence that they, like the PIAs, may also be divided into several categories. For example, the new designer drug alpha-ET produces central stimulant and DOM-like effects, as well as non-DOM-like and non- AMPH-like effects. We propose to investigate this novel agent in drug discrimination studies. Thus, in summary, we intend to further validate the 5-HT2 hypothesis of hallucinogenic drug action while, at the same time, to investigate the actions of several new and interesting structurally-related PIA and IAA designer drugs.