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)是一种旨在模拟受控物质效果的物质 以及其他滥用药物。虽然设计药物并不是一个新现象，但药物的数量和供应 SPD是史无前例的，在过去5年里急剧增加。许多致幻的SPD是 结构类似的已知5-羟色胺能致幻剂的衍生物，包括药物，如25I-NBOMe(“25- I“、”N-Bomb“)、1-丙酰-LSD和5-MeO-DALT。致幻性SPD的流行和扩散是 导致严重的公共卫生问题，因为它们通常非常有效，并构成更大的风险 毒性与较老的迷幻剂相比。因为人们对它的作用机制知之甚少 致幻性SPD的行为影响，NIDA计划公告(PAR-14-106)正在征集研究 “合成精神活性药物和抵消其有害影响的战略方法”。这 申请寻求支持的项目，以研究特定的药理机制，受体 靶点，以及介导致幻SPD行为效应的信号通路。建议数 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)，并确定它们的致幻和毒性机制 行为。使用两种互补的行为范式对啮齿动物的致幻药物效果进行评估： 探索性运动行为，这在人类研究中有直接的对应关系；以及头部抽动反应 (HTR)，这是一种迷幻剂敏感的行为测试。目标1将阐明其作用机制。 Spd类似的吲哚胺类迷幻剂，测试这些致幻SPD(包括 色胺、苯并呋喃和LSD类似物)通过5-HT1A和5-HT2A受体起作用。研究将比较 SPD效应与已知的5-羟色胺能致幻剂的图谱，并定义SPD类似物的SAR 吲哚胺类迷幻剂。目标2将阐明结构特征和第二信使系统 调节高度有效的N-苄基苯乙胺类致幻SPD的行为效应， 被称为“NBOMes”，与美斯卡林等迷幻剂有关。AIM 2研究旨在 评估(1)NBOMe的特定结构特征与它们的5-HT2A亲和力之间的联系，以及(2) 特定信号通路和5-HT2A功能选择性对这些行为效应的贡献 致幻性自闭症。目标3将评估代谢物对行为和毒理学的贡献 致幻性SPDS的影响。认为1P-LSD作为LSD的前体药物的想法以及假设 有些SPD的毒性是由于O-脱甲基代谢物将被检测。这些研究针对受体 对理解迷幻剂的拟精神效应具有重要意义的相互作用 将军。这些研究的结果将有助于预测新的SPDS和 将帮助临床医生制定策略，以减轻致幻性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.