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Pharmacology and toxicology of new psychoactive substances

新型精神活性物质的药理毒理学

基本信息

批准号：
10928567
负责人：
Michael Baumann
金额：
$ 164.28万
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/10928567
关键词：
Adverse effects Binding Biological Assay Blood Blood specimen Body Temperature Brain Catalepsy Catheters Cerebellum Conscious Data Dopamine Dose Drug Kinetics Epidemic Exposure to Fentanyl Goals Half-Life Heart Rate Human Illicit Drugs Implant In Vitro Injections Intoxication Intravenous K2/Spice Life Methods Microdialysis Molecular Mechanisms of Action Morphine Motor Activity Neurons Operative Surgical Procedures Opioid Opioid agonist Overdose Parents Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology and Toxicology Plasma Property Public Health Publications Rattus Recreation Recreational Drugs Research Research Project Grants Risk Self Administration Serotonin Sprague-Dawley Rats Stimulant Symptoms Synaptosomes Telemetry Temperature abuse liability addiction analog antinociception bath salts behavioral study biological systems blood pressure elevation cathinone clinically relevant dopamine transporter drug market drug metabolism drug of abuse drug reward experience experimental study extracellular in vivo inhibitor interest male manufacture mephedrone milligram mu opioid receptors nano natural hypothermia noradrenaline transporter novel pharmacokinetics and pharmacodynamics radioligand serotonin transporter subcutaneous synthetic cannabinoid synthetic drug synthetic opioid tandem mass spectrometry uptake

项目摘要

Summary- Substantial progress was made on this project, with the publication of six research articles about opioid and stimulant NPS. Three publications describe the pharmacology of newly emerging opioids, whereas three others highlight the effects of synthetic stimulants. The US is experiencing an unprecedented drug overdose epidemic. Illicitly manufactured fentanyl is a major factor in the overdose crisis, but a number of opioid NPS have appeared in recreation drug markets worldwide. Isotonitazene is a non-fentanyl opioid NPS associated with many intoxications and fatalities. Recent studies show that isotonitazene is a potent mu-opioid receptor (MOR) agonist in vitro, but little information is available about its in vivo effects. To this end, we examined pharmacokinetics and pharmacodynamic effects of isotonitazene in rats. Male Sprague-Dawley rats with surgically implanted intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders received isotonitazene (3 - 30 microgram/kg, s.c.) or its vehicle. Blood samples were drawn at various times for 4 h post-injection, and plasma was assayed using tandem mass spectrometry (MS/MS). Body temperature, catalepsy scores, and hot plate latencies were recorded at each blood draw. Plasma concentrations of isotonitazene rose in parallel with increasing dose (range 0.2-9.8 nanogram/mL), and half-life ranged from 30-60 min. The metabolites 4'-hydroxy nitazene and N-desethyl isotonitazene were detected, but plasma concentrations were below the limits of quantitation. Isotonitazene produced antinociception (ED50 = 4.22 microgram/kg), catalepsy-like symptoms (ED50 = 8.68 microgram/kg), and hypothermia (only at 30 microgram/kg) that were significantly correlated with concentrations of isotonitazene. The findings from our isotonitazene experiments demonstrate that the drug is a potent MOR agonist whose pharmacodynamic effects are related to circulating concentrations of the parent drug. The in vivo potency of isotonitazene to induce antinociception (ED50 = 4.22 microgram/kg) is greater than that of fentanyl (ED50 = 20 microgram/kg), and much greater than that of morphine (4.5 milligram/kg). The high potency of isotonitazene portends substantial risk to users who are exposed to the drug. Synthetic cathinones are a class of NPS that display psychomotor stimulant properties, and novel 4-chloro ring-substituted cathinones continue to emerge in illicit drug markets worldwide. We characterized the pharmacology of 4-chloro cathinone analogs, as compared to the effects of 4-methylmethcathinone (mephedrone). Synaptosomes were prepared from rat caudate for dopamine transporter (DAT) assays, or from whole brain minus caudate and cerebellum for norepinephrine transporter (NET) and serotonin transporter (SERT) assays. Findings from transporter uptake inhibition and release assays showed that mephedrone and 4-chloromethcathinone (4-CMC) function as substrates at DAT, NET, and SERT, with similar potency at all three transporters. By contrast, 4-chloro-alpha-pyrrolidinopropiophenone (4-C-alpha-PPP) was an uptake inhibitor at DAT and NET but had little activity at SERT. 4-Chloroethcathinone (4-CEC) was a low potency uptake inhibitor at DAT and NET but a substrate at SERT. In rats implanted with telemetry transmitters, mephedrone and 4-CMC increased blood pressure, heart rate, and locomotor activity to a similar extent. 4-CEC and 4-C-alpha-PPP were less potent at increasing blood pressure and had modest stimulatory effects on heart rate and activity. Our findings show that all three 4-chloro ring-substituted cathinones are biologically active, but only 4-CMC has potency comparable to mephedrone. Collectively, our results suggest that 4-CMC will have abuse potential and adverse effects in humans that are analogous to those associated with mephedrone.

摘要─ 该项目取得了实质性进展，发表了六篇关于类阿片和兴奋剂滥用的研究文章。有三份出版物描述了新出现的类阿片的药理学，另有三份出版物强调了合成兴奋剂的作用。美国正在经历前所未有的药物过量流行病。伊朗制造的芬太尼是过量危机的一个主要因素，但一些阿片类药物已出现在全球娱乐药物市场。Isotonitazene是一种非芬太尼阿片类药物，与许多中毒和死亡有关。最近的研究表明，isotonitazene是一种有效的μ-阿片受体（莫尔）激动剂在体外，但很少有关于其在体内的影响的信息。为此，我们研究了异托尼嗪在大鼠体内的药代动力学和药效学作用。雄性Sprague-Dawley大鼠，手术植入静脉内（i. v.）导管和皮下（s.c.）温度应答器接收异渗氮（3 - 30微克/kg，s.c.）或其车辆。在注射后4 h的不同时间抽取血液样品，并使用串联质谱法（MS/MS）测定血浆。每次抽血时记录体温、僵住症评分和热板潜伏期。血浆中的异渗硝唑浓度随着剂量的增加而平行升高（范围为0.2-9.8纳克/mL），半衰期范围为30-60分钟。检测到代谢物4 '-羟基硝唑和N-去乙基异渗硝唑，但血浆浓度低于定量限。异托尼氮产生的抗伤害作用（ED 50 = 4.22微克/千克），僵住样症状（ED 50 = 8.68微克/千克），和体温过低（仅在30微克/千克），与异托尼氮的浓度显着相关。我们的异渗哒嗪实验结果表明，该药物是一种有效的莫尔激动剂，其药效学效应与母体药物的循环浓度有关。在体内，异托硝唑诱导抗伤害感受的效力（ED 50 = 4.22微克/千克）大于芬太尼（ED 50 = 20微克/千克），并且远大于吗啡（4.5毫克/千克）。高效力的isotonitazene预示着暴露于该药物的使用者的巨大风险。合成卡西酮是一类具有精神兴奋剂性质的兴奋剂，新型4-氯环取代卡西酮继续出现在世界各地的非法药物市场。我们的特点是4-氯卡西酮类似物的药理学，相比4-甲基甲卡西酮（甲氧麻黄酮）的影响。从大鼠尾状核制备突触体用于多巴胺转运蛋白（DAT）测定，或从全脑减去尾状核和小脑制备突触体用于去甲肾上腺素转运蛋白（NET）和5-羟色胺转运蛋白（SERT）测定。转运蛋白摄取抑制和释放试验的结果表明，甲氧麻黄酮和4-氯甲卡西酮（4-CMC）在DAT，NET和SERT中作为底物发挥作用，在所有三种转运蛋白中具有相似的效力。相比之下，4-氯-α-吡咯烷基苯丙酮（4-C-alpha-PPP）是DAT和NET的摄取抑制剂，但在SERT几乎没有活性。4-氯乙卡西酮（4-CEC）在DAT和NET上是一种低效的摄取抑制剂，但在SERT上是一种底物。在植入遥测发射器的大鼠中，甲氧麻黄酮和4-CMC增加了血压，心率和运动活动的程度相似。 4-CEC和4-C-alpha-PPP在增加血压方面的效力较低，对心率和活动具有适度的刺激作用。我们的研究结果表明，所有三种4-氯环取代的卡西酮都具有生物活性，但只有4-CMC具有与甲氧麻黄酮相当的效力。总的来说，我们的研究结果表明，4-CMC将在人类中具有滥用潜力和不良影响，类似于与甲氧麻黄酮相关的那些。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain Concentrations of Methylone and Its Metabolites after Systemic Methylone Administration: Relationship to Pharmacodynamic Effects.

DOI：
10.1124/jpet.121.000531
发表时间：
2021-06-01
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
0
作者：
Centazzo, Nicole;Chojnacki, Michael R;Concheiro, Marta
通讯作者：
Concheiro, Marta

Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents.

DOI：
10.3390/ijms222112002
发表时间：
2021-11-05
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Tuv SS;Bergh MS;Andersen JM;Steinsland S;Vindenes V;Baumann MH;Huestis MA;Bogen IL
通讯作者：
Bogen IL

Psychoactive 'bath salts': compounds, mechanisms, and toxicities.

精神活性“浴盐”：化合物、机制和毒性。

DOI：
10.1038/npp.2012.162
发表时间：
2013
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Lehner,KurtR;Baumann,MichaelH
通讯作者：
Baumann,MichaelH

Neural and cardiac toxicities associated with 3,4-methylenedioxymethamphetamine (MDMA).