CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS

描述（由申请人提供）：我们已经证明，滥用芳基烷基胺可以在大鼠中产生至少三种不同的区别性刺激效应中的一种或多种：典型致幻剂(H)的1-（2,5-二甲氧基-4-甲基苯基）-2-氨基丙烷（D(c) m -样）效应，典型兴奋剂(S)的（+）苯丙胺类效应，第三类效应尚未得到很好的定义，但以苯烷基胺n -甲基- 1-（4-甲氧基苯基）-2-氨基丙烷（PMMA） (P)为典型。该模型暗示了三种不同的效应、三种不同的构效关系（SARs）和三种不同的作用机制。苯烷基胺致幻剂和兴奋剂的作用、非典型反应和作用机制已经得到了较好的研究。相比之下，对pmma类药物的SAR和作用机制几乎一无所知。此外，某些药物已被证明可以产生多种效果，最好将其分类为H/P-或S/P-型药物；这些药物可能通过复合机制起作用，并可能具有复合SARs。被滥用的苯乙基胺MDMA（“摇头丸”）就是这样一种药物。我们将这个agent归类为S/ p类，已知的关于它的动作和SAR与模型一致。现在正在解决的问题类型包括：mdma样药物从（+）安非他明继承了哪些结构特征，从PMMA继承了哪些结构特征？我们已经能够对抗MDMA的刺激作用；是两种MDMA的作用吗

DESCRIPTION (provided by applicant): We have shown that arylalkylamines of abuse can produce one or more of at least three distinct discriminative stimulus effects in rats: a 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane-like (D(c)M-like) effect typical of classical hallucinogens (H), a (+)amphetamine-like effect typical of stimulants (S), and a third type of effect that has not yet been well defined but is typified by the phenylalkylamine N-methyl-l-(4-methoxyphenyl)-2-aminopropane (PMMA) (P). The model implies three distinct effects, three distinct structure-activity relationships (SARs), and three distinct mechanisms of action. The actions, SARs, and mechanisms of action of phenylalkylamine hallucinogens and stimulants have been relatively well investigated. In contrast, almost nothing is known about the SAR and mechanism of action of PMMA-like agents. Furthermore, certain agents have been demonstrated to produce multiple effects and are best classified as, for example, H/P- or S/P- type agents; these agents likeiy act by composite mechanisms and likely possess composite SARs. The abused phenyiaikylamine MDMA ("Ecstasy') is such an agent. We have classified this agent as belonging to the S/P-category, and what is known about its actions and SAR are consistent with the model. Types of questions now being addressed include: What structural traits did MDMA-iike agents inherit from (+)amphetamine and which were inherited from PMMA? We have been able to antagonize the stimulus effects of MDMA; are the effects of both MDMA isomers inhibited to the same degree or by the same mechanism? Can the PMMA-stimulus be antagonized in a similar manner? Using primarily a drug discrimination paradigm [with groups of animals trained to discriminate either DOM, (+)amphetamine, PMMA, MDMA, (-)MDMA, (+)MDMA from vehicle], we propose to investigate structure-activity relationships for PMMA-like activity, to study the stimulus mechanism of action of PMMA, and to classify various agents as to the type of effect(s) they produce. For example, the actions of numerous controlled (i.e., Schedule 1) substances are poorly understood; various novel street drugs (including their metabolites and synthetic by-products) are even less well understood. Investigation of such agents not only allows their classification, it also adds to the structure-activity data being collected that can ultimately be used to forecast the actions of newer agents. Compounds necessary for the studies are proposed for synthesis. Because stereochemistry plays a key role in the actions of many of the compounds (with enantiomers sometimes producing different effects), most will be examined as individual isomers. Where agents possess two chiral centers, all four isomers will be prepared and examined. Other studies relevant to the above model include examination of the stimulus effects of DOM and MDMA metabolites. The novel classification scheme provides a platform from which mechanism of action (and mixed mechanisms of action) can be investigated and unraveled. This will eventually lead to a better understanding of abuse prevention and treatment modalities.