Preclinical medication development for stimulant use disorder

兴奋剂使用障碍的临床前药物开发

• 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
• 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

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，涉及开发治疗兴奋剂使用障碍的药物。 四篇相关论文发表在同行评审期刊上。 在一篇有趣的文章中，我们报道了新型季色胺化合物的药理学，该化合物对 5-HT2A 受体缺乏活性，但靶向血清素转运蛋白。这些发现表明某些色胺类似物可能具有抗抑郁活性，但不伴随致幻作用。 Aeruginascin（4-磷酰氧基-N,N,N-三甲基色胺）是裸盖菇素（4-磷酰氧基-N,N-二甲基色胺）的类似物，已在多种含裸盖菇素的蘑菇中发现。 我们最近报道了4-HO-TMT和4-AcO-TMT的几种季铵类似物的合成、结构表征和药理活性，即4-羟基-N,N-二甲基-N-乙基色铵（4-HO-DMET）、4-羟基-N,N-二甲基-N-正丙基色铵（4-HO-DMPT）和 4-羟基-N,N-二甲基-N-异丙基色胺（4-HO-DMiPT），以及它们假设的前药4-乙酰氧基-N,N-二甲基-N-乙基色胺（4-AcO-DMET）、4-乙酰氧基-N,N-二甲基-N-正丙基色胺（4-AcO-DMPT）和 4-乙酰氧基-N,N-二甲基-N-异丙基色铵（4-AcO-DMiPT）。使用既定方法合成化合物，并通过单晶 X 射线衍射表征结构。筛选测试化合物对多种受体和转运蛋白的体外药理活性，以确定潜在的作用靶点。这些化合物均未表现出对血清素 2A 受体 (5-HT2A) 可测量的亲和力，但几种类似物对血清素 1D 受体 (5-HT1D) 和血清素 2B 受体 (5-HT2B) 具有低微摩尔亲和力 (Ki)，它们似乎是具有低微摩尔效力的弱部分激动剂。重要的是，4-HO-DMET、4-HO-DMPT 和 4-HO-DMiPT 对血清素转运蛋白表现出亚微摩尔亲和力 (SERT；370-890 nM)。相同的 4-羟基类似物在 SERT 转染细胞 (3.3-12.3 uM) 和大鼠脑组织 (0.31-3.5 uM) 中抑制 5-HT 摄取的效力低至亚微摩尔 (IC50)。总体而言，我们的结果表明季铵类似物不靶向 5-HT2A 位点，表明这些化合物缺乏迷幻般的主观效果。然而，某些 4-羟基季色铵类似物可能为探索 SERT 选择性作用的构效关系提供新的模板。