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

下一代致幻剂：一类新型合成精神活性药物

• 批准号: 9238460
• 负责人: ADAM L. Halberstadt
• 金额: $ 33.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238460
• 关键词: Address; Affinity; Back; Basic Science; Behavior; Behavioral; Behavioral Assay; Behavioral Paradigm; Benzofurans; Binding; Brain; Cannabinoids; Cessation of life; Cytochrome P450; Designer Drugs; Development; Drug toxicity; Drug usage; Europe; HTR2A gene; Hallucinogens; Head; Human; Human Experimentation; Link; Mediating; Mescaline; Modernization; NIH Program Announcements; National Institute of Drug Abuse; Opioid; Overdose; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Phenethylamines; Physiological; Prodrugs; Psychotropic Drugs; Public Health; Research; Risk; Rodent; Rodent Model; Role; Second Messenger Systems; Serotonin; Serotonin Receptor 5-HT2A; Signal Pathway; Structure-Activity Relationship; Sympathomimetics; Testing; Time; Toxic Actions; Toxic effect; Toxicology; Tryptamines; Work; addiction; analog; base; behavioral response; cannabinoid drug; combat; design; drug of abuse; indoleamine; insight; member; neurochemistry; next generation; novel; programs; psychostimulant; receptor; response; sensory stimulus; serotonin receptor; tool

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.

项目概要 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。尽管设计药物并不是一个新现象，但设计药物的数量和可用性 SPD 是史无前例的，并且在过去 5 年里急剧增加。许多致幻 SPD 是 已知血清素致幻剂的结构相似的衍生物，包括 25I-NBOMe（“25- I”、“N-Bomb”）、1-丙酰基-LSD 和 5-MeO-DALT。致幻性 SPD 的流行和扩散是 造成严重的公共卫生问题，因为它们往往非常有效，并带来更大的风险 与较旧的致幻剂相比，其毒性更大。因为人们对其作用机制知之甚少， 致幻 SPD 的行为影响，NIDA 计划公告 (PAR-14-106) 正在征求研究 进入“合成精神活性药物和抵消其有害影响的战略方法”。这 申请寻求对研究特定药理机制、受体的项目的支持 介导致幻 SPD 行为效应的目标和信号通路。拟议的 研究计划是一项更大的合作努力的一部分，旨在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机制 行动。使用两种互补的行为范式评估啮齿类动物的致幻药物作用： 探索性运动行为，与人类研究有直接对应；和头部抽搐反应 （HTR），这是一种致幻剂敏感的行为测定。目标 1 将阐明作用机制 吲哚胺致幻剂的 SPD 类似物，检验这些致幻 SPD（包括 色胺、苯并呋喃和 LSD 类似物）通过 5-HT1A 和 5-HT2A 受体发挥作用。研究将进行比较 SPD 与已知的血清素致幻剂的效应，并定义了 SPD 类似物的 SAR 吲哚胺致幻剂。目标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”，与麦司卡林等致幻剂有关。目标 2 研究旨在 评估 (1) NBOMes 中的特定结构特征与其 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影响的贡献 致幻 SPD。目标 3 将评估代谢物对行为和毒理学的贡献 致幻 SPD 的影响。 1P-LSD 作为 LSD 前药的观点和假设 一些SPD毒性是由于O-去甲基化代谢物引起的，将进行测试。这些研究针对受体 对于理解致幻剂的拟精神病作用具有重要意义的相互作用 一般的。这些研究的结果将有助于预测新型 SPD 和药物的影响和潜在毒性。 将帮助临床医生制定策略来减轻致幻 SPD 使用的影响和后果。