Pharmacology and toxicology of new psychoactive substances

新型精神活性物质的药理毒理学

• 批准号: 10699651
• 负责人: Michael Baumann
• 金额: $ 146.16万
• 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/10699651
• 关键词: Absence of pain sensation; Adverse effects; Affinity; Agonist; Binding; Biological Assay; Blood specimen; Brain; CNR1 gene; Cannabinoids; Cannabis; Catalepsy; Conscious; Data; Dopamine; Dose; Drug Kinetics; Exhibits; Goals; Head; Heroin; Hospitalization; In Vitro; Indoles; K2/Spice; Label; Life; Measures; Medical; Membrane; Methods; Microdialysis; Molecular Mechanisms of Action; Mus; Neurons; Opioid; Overdose; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Public Health; Publications; Rattus; Recreational Drugs; Research; Research Project Grants; Risk; Self Administration; Serotonin; Stimulant; Structure-Activity Relationship; Time; abuse liability; addiction; analog; bath salts; behavioral study; biological systems; brain tissue; cannabinoid receptor; clinically relevant; drug market; drug metabolism; drug of abuse; drug reward; extracellular; in vivo; interest; natural hypothermia; pharmacokinetics and pharmacodynamics; radioligand; receptor binding; rimonabant; synthetic cannabinoid; synthetic drug; synthetic opioid

Summary- Substantial progress was made on this project, with publication of seven research articles about cannabinoid, opioid, and stimulant NPS. In particular, we characterized the pharmacokinetics and pharmacodynamics of the synthetic cannabinoid 5F-MDMB-PICA in rats. We also examined structure-activity relationships for 5F-MDMB-PICA and its analogs to produce pharmacological effects in mice. Collectively, our findings show that 5F-MDMB-PICA is an extremely potent and efficacious cannabinoid that is at least 20-fold more potent than THC, the active ingredient in cannabis. Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances found on recreational drug markets worldwide. The indole-containing compound, 5F-MDMB-PICA, is a popular SCRA associated with serious medical consequences, including overdose and hospitalizations. In vitro studies reveal that 5F-MDMB-PICA is a potent agonist at cannabinoid type 1 receptors (CB1), but little information exists regarding in vivo pharmacology of the drug. We examined the in vitro and in vivo cannabinoid-like effects produced by 5F-MDMB-PICA and related 5F-pentylindole analogs with differing composition of the head group moiety (i.e., 5F-NNEI, 5F-SDB-006, 5F-CUMYL-PICA, 5F-MMB-PICA). In mouse brain membranes, 5F-MDMB-PICA and its analogs inhibited binding to 3Hrimonabant-labeled CB1 and displayed agonist actions in 35SGTPS functional assays. 5F-MDMB-PICA exhibited the highest CB1 affinity (Ki = 1.24 nM) and functional potency (EC50 = 1.46 nM), but head group composition markedly influenced activity in both assays. For example, the 3,3-dimethylbutanoate (5F-MDMB-PICA) and cumyl (5F-CUMYL-PICA) head groups engendered high CB1 affinity and potency, whereas a benzyl (5F-SDB-006) head group did not. In C57BL/6J mice, all 5F-pentylindole SCRAs produced dose- and time-dependent hypothermia, catalepsy, and analgesia that were reversed by rimonabant, indicating CB1 involvement. In vitro Ki and EC50 values were positively correlated with in vivo ED50 potency estimates. Our findings demonstrate that 5F-MDMB-PICA is a potent SCRA, and subtle alterations to head group composition can have profound influence on pharmacological effects at CB1. Importantly, measures of CB1 binding and efficacy in mouse brain tissue seem to accurately predict in vivo drug potency in this species.

摘要─ 该项目取得了实质性进展，发表了7篇关于大麻素、阿片类药物和兴奋剂的研究文章。 特别地，我们表征了合成大麻素5 F-MDMB-PICA在大鼠中的药代动力学和药效学。 我们还研究了5 F-MDMB-PICA及其类似物在小鼠中产生药理作用的构效关系。 总的来说，我们的研究结果表明，5 F-MDMB-PICA是一种非常有效的大麻素，其效力至少是大麻中活性成分THC的20倍。 合成大麻素受体激动剂（SCRAs）是一种不断发展的新型精神活性物质，在全球娱乐药物市场上发现。含有吲哚的化合物5 F-MDMB-PICA是一种流行的SCRA，与严重的医疗后果有关，包括过量和住院治疗。体外研究表明，5 F-MDMB-PICA是大麻素1型受体（CB 1）的有效激动剂，但关于该药物的体内药理学的信息很少。我们检查了由5 F-MDMB-PICA和具有不同组成的头部基团部分的相关5 F-戊基吲哚类似物（即，5F-NNEI、5F-SDB-006、5F-PICA、5F-MMB-PICA）。在小鼠脑膜中，5 F-MDMB-PICA及其类似物抑制与3 Hrimonabant标记的CB 1的结合，并在35 SGTPS功能测定中显示激动剂作用。5 F-MDMB-PICA表现出最高的CB 1亲和力（Ki = 1.24 nM）和功能效力（EC 50 = 1.46 nM），但头基组成在两种测定中显著影响活性。例如，3，3-二甲基丁酸酯（5 F-MDMB-PICA）和枯基（5 F-Cumyl-PICA）头部基团产生高的CB 1亲和力和效力，而苄基（5 F-SDB-006）头部基团则没有。在C57 BL/6 J小鼠中，所有5 F-戊基吲哚SCRA产生剂量和时间依赖性体温过低、僵住和镇痛，这些都被利莫那班逆转，表明CB 1参与。体外Ki和EC 50值与体内ED 50效价估计值呈正相关。我们的研究结果表明，5 F-MDMB-PICA是一种有效的SCRA，头基组成的细微变化可能对CB 1的药理作用产生深远的影响。重要的是，小鼠脑组织中CB 1结合和功效的测量似乎可以准确预测该物种的体内药物效力。