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

 描述(由申请人提供)：国家药物滥用研究所认识到，滥用合成卡西诺酮(SC)是一个严重的公共卫生问题。SC的使用会导致恐慌、精神病、神经并发症、心脏和肾脏毒性，以及致命的过量用药。SC是苯丙胺的β-酮类似物，具有与其对应的苯丙胺类似的主观作用(例如，兴奋剂和致幻作用)。然而，人类报告了苯丙胺和SC在心理作用上的显著差异，强调SC是一种独特的药物类别，具有独特的药理特性和神经生物学效应，其中许多目前尚不清楚。随着最近许多被广泛滥用的SC的DEA调度，如甲氧麻黄酮、亚甲基二氧基吡喃酮(MDPV)和甲酮，出现了第二代SC，其中大多数SC含有吡咯烷部分，取代了第一代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并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，这表明除了单胺转运体外，它们可能还通过受体系统起作用。然而，缺乏测试吡咯烷SC的恐惧诱导效应的系统研究，而且有必要对可能导致精神事件的受体进行吡咯烷SC的系统药理学评估。此外，到目前为止，还没有批准的药物治疗急性SC过量，但我们的初步数据表明，5-HT2A受体拮抗剂是一种有希望的新的药物干预措施，可以减轻精神刺激剂引起的精神病、高热、惊厥和致命的过量用药。我们拟议的研究将比较新的和广泛获得的第二代吡咯烷SC和甲麻黄酮，并将确定：1)吡咯烷替代如何影响HEK293细胞中表达的5-羟色胺5-羟色胺和肾上腺素能α1受体亚型的亲和力和功能；2)吡咯烷替代是否有助于小鼠的恐惧、焦虑和精神病；以及3)5-HT2和α1选择性配体阻断急性SC过量的临床关键成分的有效性。AIMS 1和AIMS 2中的实验将解决这一公共资金公告的目标，以提供关于SC的药理和独特作用的信息。AIM 3的结果将指导发现治疗急性SC过量的新的速效疗法。

 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.