The Next Generation of Hallucinogens: A New Class of Synthetic Psychoactive Drugs

项目摘要 合成精神活性药物（SPD）是旨在模仿受控物质效果的物质 和其他滥用药物。虽然设计师药物不是一个新现象， SPD是前所未有的，在过去5年中急剧增加。许多致幻性SPD 结构上类似的已知的多巴胺能致幻剂的衍生物，包括药物如25 I-NBOMe（“25-NBOMe”）， I”、“N-Bomb”）、1-丙酰基-LSD和5-MeO-DALT。致幻SPD的流行和扩散是 造成重大的公共卫生问题，因为它们往往是高度有效的，并构成更大的风险， 与旧的致幻剂相比毒性。由于对作用机制知之甚少， 致幻SPD的行为影响，NIDA计划公告（PAR-14-106）正在征求研究 “合成精神活性药物和战略方法，以抵消其有害影响。”这 申请寻求对一个项目的支持，以调查特定的药理机制，受体 靶点，以及介导致幻SPD行为效应的信号通路。拟议 研究计划是更大的合作努力的一部分，以快速识别和表征新的SPD，定义 它们的构效关系（SAR），并确定其致幻和毒性的机制 行动使用两种互补的行为模式评估啮齿动物中的致幻药物效应： 探索性运动行为，在人类研究中有直接的对应物;以及头部抽搐反应 (HTR)，这是一种对致幻剂敏感的行为测定。目的1将阐明的作用机制， 吲哚胺致幻剂的SPD类似物，测试这些致幻SPD（包括 色胺、苯并呋喃和LSD类似物）通过5-HT 1A和5-HT 2A受体起作用。研究将比较 SPD效应与已知的多巴胺能致幻剂的特征，并定义了多巴胺能致幻剂SPD类似物的SAR。 吲哚胺致幻剂目的2将阐明结构特征和第二信使系统 介导高效N-苄基苯乙胺类致幻SPD的行为效应， 被称为“NBOMes”，与致幻剂如美斯卡灵有关。目标2研究旨在 评估（1）NBOMes的特定结构特征与其5-HT 2A亲和力之间的联系，以及（2） 特定的信号通路和5-HT 2A功能选择性对这些行为效应的贡献 致幻性SPD目标3将评估代谢物对行为和毒理学的贡献 致幻SPD的效果1 P-LSD作为LSD的前药的想法和假设， 一些SPD毒性是由于O-脱甲基代谢物引起的。这些研究涉及受体 这些相互作用对于理解致幻剂的拟精神作用具有重要意义， 将军这些研究的结果将有助于预测新SPD的作用和潜在毒性， 将帮助临床医生制定策略，以减轻致幻SPD使用的影响和后果。

Project Summary Synthetic Psychoactive Drugs (SPDs) are substances designed to mimic the effects of controlled substances and other abused drugs. Although designer drugs are not a new phenomenon, the number and availability of SPDs is unprecedented and has increased dramatically over the last 5 years. Many hallucinogenic SPDs are structurally similar derivatives of known serotonergic hallucinogens, including drugs such as 25I-NBOMe (“25- I”, “N-Bomb”), 1-propionyl-LSD, and 5-MeO-DALT. The popularity and proliferation of hallucinogenic SPDs is causing a significant public health problem because they are often highly potent and pose greater risks of toxicity compared with older hallucinogens. Because very little is known about the mechanisms of action and behavioral effects of hallucinogenic SPDs, a NIDA program announcement (PAR-14-106) is soliciting research into “Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects.” This application seeks support for a project to investigate the specific pharmacological mechanisms, receptor targets, and signaling pathways that mediate the behavioral effects of hallucinogenic SPDs. The proposed research program is part of a larger collaborative effort to rapidly identify and characterize new SPDs, define their structure-activity relationships (SAR), and determine the mechanisms of their hallucinogenic and toxic actions. Hallucinogenic drug effects in rodents are assessed using two complementary behavioral paradigms: exploratory locomotor behavior, which has a direct counterpart in human studies; and the head twitch response (HTR), which is a hallucinogen-sensitive behavioral assay. Aim 1 will elucidate the mechanisms of action of SPD analogs of indoleamine hallucinogens, testing the hypothesis that these hallucinogenic SPDs (including tryptamines, benzofurans, and LSD analogs) act through 5-HT1A and 5-HT2A receptors. Studies will compare SPD effects with the known profiles of serotonergic hallucinogens and define the SAR of SPD analogs of indoleamine hallucinogens. Aim 2 will elucidate the structural features and second messenger systems mediating the behavioral effects of the highly potent N-benzylphenethylamine class of hallucinogenic SPDs, known as “NBOMes,” that are related to hallucinogens such as mescaline. Aim 2 studies are designed to assess (1) the link between specific structural features in NBOMes and their 5-HT2A affinities, and (2) the contributions of specific signaling pathways and 5-HT2A functional selectivity to the behavioral effects of these hallucinogenic SPDs. Aim 3 will assess the contributions of metabolites to the behavioral and toxicological effects of hallucinogenic SPDs. The idea that 1P-LSD acts as a pro-drug for LSD and the hypothesis that some SPD toxicity is due to O-demethylated metabolites will be tested. These studies address receptor interactions that have important implications for understanding the psychotomimetic effects of hallucinogens in general. The results of these studies will aid in predicting the effects and potential toxicities of new SPDs and will help clinicians to develop strategies to mitigate the effects and consequences of hallucinogenic SPD use.