Receptor pharmacology and toxicology of second-generation pyrrolidine "bath salt" cathinones

第二代吡咯烷“浴盐”卡西酮的受体药理学和毒理学

基本信息

批准号：
9295002
负责人：
CLINTON E CANAL
金额：
$ 22.35万
依托单位：
MERCER UNIVERSITY MACON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295002
关键词：
Acute Address Adrenergic Agents Affect Affinity Agonist Amination Amines Amphetamines Anxiety Bathing Behavioral Biological Assay Cardiac Cardiotoxicity Catecholamines Cells Cessation of life Clinical Controlled Study Convulsions Data Dose Event Fright Funding G-Protein-Coupled Receptors Generations Goals HTR2A gene Human Hypertension Hyperthermia Intervention Ketones Kidney Ligands Measures Metabolism Mus National Institute of Drug Abuse Neurobiology Neurologic Overdose Panic Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Pharmacotherapy Property Psychotic Disorders Public Health Pyrrolidines Regulation Reporting Research Infrastructure Risk Schedule Serotonin Serotonin Receptor 5-HT2A Serotonin Receptor 5-HT2C Signal Transduction Sodium Chloride System Testing Toxic effect analog authority base cathinone chemical addition chemical group chemical substitution experimental study guided inquiry in vivo monoamine mortality novel pre-clinical psychologic psychostimulant public health relevance receptor response vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): The National Institute on Drug Abuse recognizes that the abuse of synthetic cathinones (SC) is a serious public health issue. SC use can cause panic, psychosis, neurological complications, cardiac and renal toxicity, and fatal overdose. SC is β-ketone analogs of amphetamines, and have similar subjective effects (e.g., stimulant and hallucinogenic effects) as their respective amphetamine counterparts. However, humans report conspicuous differences in psychological effects between amphetamines and SC, highlighting that SC is a unique drug class with unique pharmacological properties and neurobiological effects, much of which are presently unknown. With the recent DEA scheduling of many widely abused SC, e.g. mephedrone, methylenedioxypyrovalerone (MDPV), and methylone, second-generation SC have emerged, most of which contain a pyrrolidine moiety in place of the secondary amine of first-generation SC. MDPV was the first of the pyrrolidine SC to gain popularity among stimulant users, however, due to MDPV's scheduling with other first-generation SC, illicit chemists have synthesized and distributed many other pyrrolidine SC. Pyrrolidine SC appear to have an unusually high propensity to induce panic and psychosis, which suggests they may be acting through receptor systems in addition to monoamine transporters. However, systematic studies testing the fear-inducing effects of pyrrolidine SC are lacking, and systematic pharmacological assessments of pyrrolidine SC at receptors that could contribute to psychiatric events are warranted. Also, to date, no approved medications exist for acute SC overdose, but our preliminary data demonstrate a promising, new pharmacological intervention, 5-HT2A receptor antagonism, to mitigate psychostimulant-induced psychosis, hyperthermia, convulsions, and fatal overdose. Our proposed studies will compare new and widely available, second-generation pyrrolidine SC to mephedrone and will determine: 1) how the pyrrolidine substitution affects affinity and function at serotonin 5-HT2 and adrenergic α1 receptor subtypes expressed in HEK293 cells; 2) whether the pyrrolidine substitution contributes to fear, anxiety, and psychosis in mice; and 3) the efficacy of 5-HT2 and α1 selective ligands to block clinically critical components of acute SC overdose in mice. The experiments in Aims 1 and 2 will address the goal of this public funding announcement to provide information regarding the pharmacology and unique effects of SC. The results from Aim 3 will guide discovery of novel fast-acting treatments for acute SC overdose.

描述（由申请人提供）：国家药物滥用研究所认识到合成卡西酮 (SC) 的滥用是一个严重的公共卫生问题。 SC 的使用可能导致恐慌、精神病、并发症、心脏和肾脏毒性以及致命的 SC 过量。是苯丙胺的 β-酮类似物，与各自的苯丙胺对具有相似的主观作用（例如兴奋和致幻作用），但人类报告存在显着差异。安非他明和 SC 之间的心理影响，强调 SC 是一种独特的药物类别，具有独特的药理学特性和神经生物学作用，其中许多作用目前尚不清楚。已经出现了第二代SC，其中大部分含有吡咯烷部分代替第一代MDPV的仲胺。吡咯烷 SC 受到兴奋剂使用者的欢迎，然而，由于 MDPV 与其他第一代 SC 的调度，非法化学家已经合成并分发了许多其他吡咯烷 SC 似乎具有异常高的诱发恐慌和精神病的倾向，这表明。除了单胺转运蛋白外，它们还可能通过受体系统发挥作用。然而，缺乏测试吡咯烷 SC 的恐惧诱导作用的系统研究，也缺乏系统的药理学评估。此外，迄今为止，还没有批准用于急性皮下注射过量的药物，但我们的初步数据表明，一种有前景的新药理干预措施，即 5-HT2A 受体拮抗剂，可以减轻精神兴奋剂引起的症状。我们提出的研究将比较新的和广泛使用的第二代吡咯烷 SC 与甲氧麻黄酮，并确定：1）如何吡咯烷取代会影响 HEK293 细胞中表达的血清素 5-HT2 和肾上腺素能 α1 受体亚型的亲和力和功能；2) 吡咯烷取代是否会导致小鼠的恐惧、焦虑和精神病；3) 5-HT2 和 α1 选择性的功效；目标 1 和 2 中的实验将解决本公开资助公告的目标：有关 SC 药理学和独特作用的信息 Aim 3 的结果将指导发现针对急性 SC 过量的新型速效治疗方法。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice.

DOI：
10.1016/j.ejphar.2018.11.003
发表时间：
2019-01-05
期刊：
European journal of pharmacology
影响因子：
5
作者：
Murphy TJ;Murnane KS
通讯作者：
Murnane KS

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo.

肾上腺素受体拮抗剂卡维地洛在体外和体内均与血清素 2A 受体相互作用。

DOI：
10.1016/j.pbb.2019.04.003
发表时间：
2019
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
0
作者：
Murnane,KevinSean;Guner,OsmanF;Bowen,JPhillip;Rambacher,KalynM;Moniri,NaderH;Murphy,TylerJ;Daphney,CedrickMaceo;Oppong-Damoah,Aboagyewaah;Rice,KennerC
通讯作者：
Rice,KennerC

Effects of the second-generation "bath salt" cathinone alpha-pyrrolidinopropiophenone (α-PPP) on behavior and monoamine neurochemistry in male mice.

DOI：
10.1007/s00213-018-5044-z
发表时间：
2019-03
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Ray A;Chitre NM;Daphney CM;Blough BE;Canal CE;Murnane KS
通讯作者：
Murnane KS

Effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice.

合成迷幻剂 2,5-二甲氧基-4-碘苯丙胺 (DOI) 对雄性小鼠乙醇消耗和位置调节的影响。

DOI：
10.1007/s00213-019-05328-7
发表时间：
2019
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Oppong-Damoah,Aboagyewaah;Curry,KristenE;Blough,BruceE;Rice,KennerC;Murnane,KevinS
通讯作者：
Murnane,KevinS

The Endocannabinoid System and Alcohol Dependence: Will Cannabinoid Receptor 2 Agonism be More Fruitful than Cannabinoid Receptor 1 Antagonism?

内源性大麻素系统和酒精依赖性：大麻素受体 2 激动作用会比大麻素受体 1 拮抗作用更有效吗？