CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS

致幻剂的化学/行为研究

• 批准号: 7050224
• 负责人: RICHARD A GLENNON
• 金额: $ 29.3万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050224
• 关键词: 2,5 dimethoxy 4 methylamphetamine; 3,4 methylenedioxymethamphetamine; N hydroxylation; chemical structure function; chemical synthesis; hallucinogens; isomer; laboratory rat; methamphetamine; methoxamine; methylation; methylphenidate; pharmacokinetics; psychopharmacology; radiotracer; substance abuse related behavior

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.

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：经典致幻剂典型的 1-(2,5-二甲氧基-4-甲基苯基)-2-氨基丙烷样（D(c)M 样）效应 (H)，兴奋剂典型的 (+) 苯丙胺样效应 (S)，第三种效应尚未明确定义，但以苯基烷基胺 N-甲基-1-(4-甲氧基苯基)-2-氨基丙烷 (PMMA) (P) 为代表。该模型暗示了三种不同的效应、三种不同的结构-活性关系（SAR）和三种不同的作用机制。苯烷基胺致幻剂和兴奋剂的作用、SAR 和作用机制已得到相对充分的研究。相比之下，人们对 PMMA 类制剂的 SAR 和作用机制几乎一无所知。此外，某些药剂已被证明可产生多种效果，最好分类为，例如，H/P-或S/P-型药剂；这些代理可能通过复合机制起作用，并且可能拥有复合 SAR。被滥用的苯烷基胺 MDMA（“摇头丸”）就是这样一种药剂。我们已将这种药剂归类为 S/P 类，并且已知的其作用和 SAR 与模型一致。现在正在解决的问题类型包括： MDMA 类药剂从 (+) 安非他明继承了哪些结构特征，哪些是从 PMMA 继承的？我们已经能够拮抗 摇头丸； MDMA 的作用 异构体受到相同程度或通过相同机制的抑制？ PMMA刺激能以类似的方式被拮抗吗？主要使用药物辨别范式[对动物组进行训练以区分媒介物中的 DOM、(+) 安非他明、PMMA、MDMA、(-)MDMA、(+)MDMA]，我们建议研究 PMMA 样活性的结构-活性关系，研究 PMMA 的刺激作用机制，并根据其产生的效应类型对各种药物进行分类。例如，人们对多种受控物质（即附表 1）的作用知之甚少；各种新型街头毒品（包括其代谢物和合成副产品）的了解甚至更少。对此类智能体的研究不仅可以对其进行分类，还可以增加所收集的结构活动数据，这些数据最终可用于预测新智能体的行为。建议合成研究所需的化合物。由于立体化学在许多化合物的作用中起着关键作用（对映体有时会产生不同的效果），因此大多数化合物将作为单独的异构体进行检查。如果试剂具有两个手性中心，则将制备并检查所有四种异构体。与上述模型相关的其他研究包括检查 DOM 和 MDMA 代谢物的刺激效应。新颖的分类方案提供了一个可以研究和阐明作用机制（以及混合作用机制）的平台。这最终将导致人们更好地了解虐待的预防和治疗方式。