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B CARBOLINE HALLUCINOGENS

B 碳氢化合物致幻剂

基本信息

批准号：
2897935
负责人：
RICHARD A GLENNON
金额：
$ 18.1万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2001-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2897935
关键词：
2,5 dimethoxy 4 methylamphetamine chemical structure function chemical synthesis hallucinogens laboratory rat neuropharmacology neurotransmitter agonist neurotransmitter antagonist pyridoindole receptor binding serotonin receptor stimulus generalization tissue /cell culture tryptamines

项目摘要

The beta-carboline hallucinogens remain as the last category of classical hallucinogenic agents that has not been studied in a systematic and comprehensive manner. These agents, which have been termed fantasy- enhancing agents, are receiving increased attention in the media. Due to their relative ease of synthesis, and because of a resurgent interest in hallucinogenic agents, the beta-carboline hallucinogens may either prove to be future drugs of abuse in this country or may serve as templates for the development of new designer drugs. Little is known about their structure-activity relationships (SAR) and essentially nothing is known regarding their mechanism of action. The beta-carboline hallucinogens, because they possess an indolealkylamine nucleus, have been categorized as classical hallucinogens (i.e. members of a hallucinogen family to which the indolealkylamine LSD, and the phenalkylamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane or DOM, belong). Because significant progress has been made in recent years with respect to understanding the SAR and mechanism of action of classical hallucinogens, it may be extra olate or apply this information to the beta-carboline hallucinogens if, indeed, they can be demonstrated to be members of the same hallucinogen family. Preliminary data suggest that some beta-carbolines do behave like classical hallucinogens whereas other data indicate that differences may exist. That is, what little SAR results are available are inconsistent with what is known about other classical hallucinogens; and yet, two examples of beta-carboline hallucinogens (i.e. harmaline and 6- methoxyharmalan), like (+ )LSD, produce stimulus effects similar to those produced by DOM. The overall goals of this study are to systematically examine beta-carboline hallucinogens and to identify their SAR and to determine if they act via a mechanism common to other classical hallucinogens or via a unique mechanism of action. To this extent, drug discrimination studies employing rats as subjects, and radioligand binding to determine receptor affinity, will be undertaken. Specifically, tests of stimulus generalization and stimulus antagonism will be conducted with animals trained to discriminate harmaline from vehicle in order to identify stimulus mechanisms of action, tests of stimulus generalization will be conducted with animals trained to discriminate either DOM or harmaline from vehicle to determine similarity of stimulus effects, and radioligand binding studies will be performed, and correlations attempted with stimulus potency, to see if relationships exist as they do with other classical hallucinogens. Compounds required to test specific hypotheses are planned for synthesis. Pharmacological and SAR comparisons will be made with other classical hallucinogens and with non-hallucinogenic beta- carbolines. Because preliminary data suggest that certain of these agents bind at serotonin and tryptamine receptors, the project will initially focus on these two neurotransmitter mechanisms.

β-咔啉致幻剂仍然是最后一类经典的致幻剂，尚未在系统和全面的方式。这些代理人，被称为幻想- 增强剂在媒体中受到越来越多的关注。由于他们的合成相对容易，而且由于对 β-咔啉致幻剂可能证明成为这个国家未来的滥用药物，或者可以作为模板，新设计药物的开发很少有人知道他们构效关系（SAR），基本上一无所知关于他们的行动机制。β-咔啉致幻剂因为它们具有吲哚烷基胺核，已被分类为经典的致幻剂（即致幻剂家族的成员，吲哚烷基胺LSD和苯烷基胺1-（2，5-二甲氧基-4- 甲基苯基）-2-氨基丙烷或DOM，属于）。因为重大进展近年来，在了解特区方面取得了很大进展，经典致幻剂的作用机制，它可能是额外的或将这些信息应用于β-咔啉致幻剂，如果，确实，它们可以被证明是同一个致幻剂家族的成员。初步数据表明，一些β-咔啉确实表现得像传统的致幻剂，而其他数据表明，存在.也就是说，可用的SAR结果很少，与已知的其他经典致幻剂;然而，两个 β-咔啉致幻剂的实例（即，甲氧哈马兰），如（+）LSD，产生刺激作用类似于那些由DOM制作。本研究的总体目标是系统地检查β-咔啉致幻剂，并确定其SAR，确定它们是否通过与其他经典方法相同的机制起作用致幻剂或通过独特的作用机制。在这种情况下，药物采用大鼠作为受试者的鉴别研究，以确定受体亲和力。具体而言，测试刺激泛化和刺激拮抗将进行，训练动物区分骚扰者和车辆，识别刺激作用机制，测试刺激泛化将使用经过训练的动物进行，以区分DOM或来自溶剂的骆驼蓬碱以确定刺激作用的相似性，以及将进行放射性配体结合研究，并尝试相关性与刺激的效力，看看是否存在关系，因为他们与其他典型的致幻剂测试特定假设所需的化合物计划进行合成。药理学和SAR比较将与其他传统致幻剂和非致幻剂β- 咔啉因为初步数据显示，结合血清素和色胺受体，该项目最初将重点关注这两种神经递质机制。