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

• 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
• 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

 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使用可导致恐慌、精神病、神经系统并发症、心脏和肾脏毒性以及致命的过量。SC是安非他明的β-酮类似物，并且具有类似的主观效应（例如，兴奋剂和致幻作用）。然而，人类报告安非他明和SC之间的心理效应存在显着差异，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效应，其中大部分目前尚不清楚。随着最近DEA调度许多广泛滥用的SC，例如甲氧麻黄酮，亚甲二氧基吡咯戊酮（MDPV）和甲酮，第二代SC已经出现，其中大多数含有吡咯烷部分代替第一代SC的仲胺。MDPV是第一个在兴奋剂使用者中流行的吡咯烷SC，然而，由于MDPV与其他第一代SC的调度，非法化学家已经合成和分发了许多其他吡咯烷SC。吡咯烷SC似乎具有异常高的诱发恐慌和精神病的倾向，这表明它们可能通过除了单胺转运蛋白之外的受体系统起作用。然而，缺乏对吡咯烷SC的恐惧诱导作用的系统性研究，需要对吡咯烷SC在可能导致精神病事件的受体进行系统性药理学评估。此外，到目前为止，还没有批准用于急性SC过量的药物，但我们的初步数据表明，5-HT 2A受体拮抗剂是一种有前景的新药理学干预，可减轻精神兴奋剂诱导的精神病、高热、惊厥和致死性过量。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，并将确定：1）吡咯烷取代如何影响HEK 293细胞中表达的5-羟色胺5-HT 2和肾上腺素能α1受体亚型的亲和力和功能; 2）吡咯烷取代是否有助于小鼠的恐惧，焦虑和精神病;和3）5-HT 2和α1选择性配体阻断小鼠急性SC过量的临床关键组分的功效。目标1和2中的实验将解决这一公共资金公告的目标，以提供有关SC的药理学和独特作用的信息。目标3的结果将指导发现急性SC过量的新型速效治疗方法。

项目成果

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
• 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？

• DOI: 10.2174/1871527320666210211115007
• 发表时间: 2022
• 期刊: CNS & neurological disorders drug targets
• 作者: Oppong-Damoah,Aboagyewaah;Gannon,BrendaMarie;Murnane,KevinSean
• 通讯作者: Murnane,KevinSean