Preclinical medication development for stimulant use disorder

兴奋剂使用障碍的临床前药物开发

基本信息

批准号：
10699650
负责人：
Michael Baumann
金额：
$ 62.64万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699650
关键词：
Acute Advocate Affinity Agonist Antidepressive Agents Anxiety Biological Assay Brain Carrier Proteins Cells Clinical Research Cocaine Cognition Crystallization Development Dopamine Exhibits FDA approved Fentanyl HTR2A gene Hallucinogens Hybrids Illicit Drugs In Vitro Ingestion Investigation Journals Laboratories Ligands Long-Term Effects Measurable Mediating Mental Depression Methadone Methamphetamine Methods N,N-Dimethyltryptamine Neurobiology Paper Peer Review Perception Pharmaceutical Preparations Pharmacology Pharmacotherapy Prodrugs Property Publishing Rattus Reporting Research Rodent Model Self Administration Serotonin Serotonin Receptor 5-HT1D Serotonin Receptor 5-HT2A Serotonin Receptor 5-HT2B Severities Site Stimulant Structure Structure-Activity Relationship Substance Use Disorder Testing Therapeutic Effect Tryptamines United States Work X ray diffraction analysis abuse liability analog base brain tissue cigarette smoking dopamine transporter drug development drug of abuse drug seeking behavior extracellular heroin use medication administration monoamine nicotine gum novel overdose death pre-clinical receptor serotonin transporter stimulant dependence stimulant use stimulant use disorder synthetic opioid tryptamine analog uptake

项目摘要

Summary- Significant progress was made on this project, which involves the development of medications for stimulant use disorders. Four relevant papers were published in peer-reviewed journals. In one interesting article, we report the pharmacology of novel quaternary tryptamine compounds which are devoid of activity at 5-HT2A receptors but target serotonin transporters. These findings suggest that certain tryptamine analogs might have antidepressant activity without accompanying psychedelic effects. Aeruginascin (4-phosphoryloxy-N,N,N-trimethyltryptammonium) is an analogue of psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) that has been identified in several species of psilocybin-containing mushrooms. We recently reported the synthesis, structural characterization, and pharmacological activity of several quaternary tryptammonium analogues of 4-HO-TMT and 4-AcO-TMT, namely, 4-hydroxy-N,N-dimethyl-N-ethyltryptammonium (4-HO-DMET), 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium (4-HO-DMPT), and 4-hydroxy-N,N-dimethyl-N-isopropyltryptammonium (4-HO-DMiPT), as well as their hypothesized prodrugs 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium (4-AcO-DMET), 4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium (4-AcO-DMPT), and 4-acetoxy-N,N-dimethyl-N-isopropyltryptammonium (4-AcO-DMiPT). Compounds were synthesized using established methods, and structures were characterized by single-crystal X-ray diffraction. Test compounds were screened for in vitro pharmacological activity at a variety of receptors and transporters to determine potential targets of action. None of the compounds exhibited measurable affinity for the serotonin 2A receptor (5-HT2A), but several analogues had low micromolar affinity (Ki) for the serotonin 1D receptor (5-HT1D) and serotonin 2B receptor (5-HT2B), where they appeared to be weak partial agonists with low micromolar potencies. Importantly, 4-HO-DMET, 4-HO-DMPT, and 4-HO-DMiPT displayed sub-micromolar affinity for the serotonin transporter (SERT; 370-890 nM). The same 4-hydroxy analogues had low to sub-micromolar potencies (IC50) for inhibition of 5-HT uptake at SERT in transfected cells (3.3-12.3 uM) and rat brain tissue (0.31-3.5 uM). Overall, our results show that quaternary tryptammonium analogues do not target 5-HT2A sites, suggesting the compounds lack psychedelic-like subjective effects. However, certain 4-hydroxy quaternary tryptammonium analogues may provide novel templates for exploring structure-activity relationships for selective actions at SERT.

概括- 该项目取得了重大进展，其中涉及开发用于刺激使用障碍的药物。在同行评审期刊上发表了四篇相关论文。在一篇有趣的文章中，我们报告了新型四胺化合物化合物的药理学，这些化合物在5-HT2A受体上没有活性，但靶向5-羟色胺转运蛋白。这些发现表明，某些色氨酸类似物可能具有抗抑郁活性而不会伴随着迷幻作用。铜绿素蛋白（4-磷酸氧基N，N，N-三甲基trytryptammonium）是psilocybin（4-磷酸氧基N，N-二甲基trytrtryptamine）的类似物，已在几种含psilocybin的蘑菇中被鉴定出来。我们最近报道了4-HO-TMT和4-ACO-TMT的几个五氨基类似物的合成，结构表征和药理活性4-羟基-N，N-二甲基-N-异丙基tryptryptammonium（4-HO-DMIPT）及其假设的前药4-乙酰氧基-N，N-二甲基n-乙基甲基trytrtryptammonium（4-Acetoxo-Dmonium（4- acotoxoxy），4-乙酰氧基），4-乙酰基-N-N-N-N-N---二甲基 - 北核基 - n-- n-N-n---------------- 4-乙酰氧基-N，N-二甲基-N-异丙基四铵（4-ACO-DMIPT）。使用已建立的方法合成化合物，结构以单晶X射线衍射为特征。对测试化合物在各种受体和转运蛋白上的体外药理活性进行筛选，以确定潜在的作用靶标。这些化合物均未表现出对5-羟色胺2A受体（5-HT2A）的可测量亲和力，但几个类似物的微摩尔亲和力（Ki）对于5-羟色胺1D受体（5-HT1D）和5- ht1d）和5-羟色胺2B受体（5-HT2B）的亲和力（Ki），似乎是与低微摩尔摩尔运动型弱型agonists的弱点。重要的是，4-HO-DMET，4-HO-DMPT和4-HO-DMIPT显示了5-羟色胺转运蛋白的亚微摩尔亲和力（SERT； 370-890 nm）。相同的4-羟基类似物具有抑制转染细胞（3.3-12.3 um）和大鼠脑组织（0.31-3.5 um）的SERT抑制5-HT摄取的抑制5-HT摄取的低到微摩尔电势（IC50）。总体而言，我们的结果表明，第四纪色锥类似物不是针对5-HT2A位点，这表明这些化合物缺乏迷幻的主观效应。但是，某些4-羟基五粒细纹类似物类似物可能会为探索SERT选择性作用的结构活性关系提供新的模板。