Structural determinants of abuse-related effects of synthetic cathinone analogs

说明（由申请人提供）：卡西酮和甲卡西酮分别是安非他明和甲基安非他明的β-酮类似物，并且像它们的安非他明类似物一样，卡西酮和甲卡西酮起单胺释放剂的作用，其选择性地促进多巴胺（DA）和去甲肾上腺素（NE）的释放超过5-羟色胺（5-HT）.卡西酮和甲卡西酮产生类似安非他明的精神兴奋剂作用，被美国缉毒局列为附表一滥用药物。最近，合成卡西酮类似物已在欧洲和美国作为滥用的特制药物出现，并以“浴盐”等看似无害的名称销售，试图逃避法律的限制。这些危险的、最近出现的和新型的滥用药物显示出不同的选择性，以促进DA/NE相对于5-HT的释放，并且对DA神经传递的选择性被认为与滥用倾向相关。这项F30申请提出了临床前研究，以检查合成卡西酮浴盐产生的滥用相关行为和神经化学作用的结构决定因素。“为了评估卡西酮衍生物的滥用相关兴奋剂作用的结构决定因素，本申请将 集中于甲卡西酮骨架的一个特征：苯环的帕拉取代基。一系列的六个新的甲卡西酮衍生物将被检查，以评估如何的物理化学参数（空间体积，亲脂性和供电子/吸电子能力）的甲卡西酮衍生物的帕拉取代基的影响，在体外单胺转运蛋白的选择性，以及在体内的神经化学和行为的影响。我们假设帕拉取代基的电子特征将与神经化学选择性相关，以促进DA与5-HT释放，如通过体内微透析和行为选择性产生滥用相关的影响，如通过颅内自我刺激（ICSS）。该项目的完成将使人们更好地了解合成卡西酮类似物滥用相关效应的机制，从而能够开发治疗“浴盐”中毒的新策略，并改善与“浴盐”滥用相关的临床结果。

DESCRIPTION (provided by applicant): Cathinone and methcathinone are the ß-ketone analogs of amphetamine and methamphetamine, respectively, and like their amphetamine analogs, cathinone and methcathinone function as monoamine releasers that selectively promote the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). Cathinone and methcathinone produce amphetamine-like, psychostimulant effects and are classified as Schedule I drugs of abuse by the United States Drug Enforcement Agency (DEA). Recently, synthetic cathinone analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like "bath salts" in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse display varying selectivity to promote release of DA/NE vs. 5-HT, and selectivity for DA neurotransmission is believed to correlate with abuse liability. This F30 application proposes preclinical research to examine the structural determinants of abuse-related behavioral and neurochemical effects produced by synthetic cathinone "bath salts." To evaluate structural determinants of the abuse-related stimulant effects of cathinone derivatives, this application will focus on one feature of the methcathinone scaffold: the para substituent of the benzene ring. A series of six novel methcathinone derivatives will be examined in order to evaluate how physicochemical parameters (steric volume, lipophilicity and electron-donating/withdrawing capacity) of the para substituent of methcathinone derivatives influence in vitro monoamine transporter selectivity as well as in vivo neurochemical and behavioral effects. We hypothesize that electronic features of the para substituent will correlate with neurochemical selectivity to promote DA vs. 5-HT release as determined by in vivo microdialysis and behavioral selectivity to produce abuse-related effects as determined by intracranial self-stimulation (ICSS). Completion of this project will provide an improved understanding of the mechanism of synthetic cathinone analogs' abuse-related effects, allowing for development of novel strategies for treating "bath salts" intoxication and improvement of clinical outcomes associated with "bath salts" abuse.