Structural determinants of abuse-related effects of synthetic cathinone analogs

描述(申请人提供)：卡西酮和美卡西酮分别是安非他明和甲基苯丙胺的伯酮类似物，与它们的苯丙胺类似物一样，卡西酮和美卡西酮作为单胺释放剂，选择性地促进多巴胺(DA)和去甲肾上腺素(NE)通过5-羟色胺(5-羟色胺)的释放。卡西酮和美卡西酮产生类似安非他明的精神刺激作用，被美国禁毒署(DEA)列为第一类滥用药物。最近，在欧洲和美国，合成卡西酮类似物已经成为滥用药物的设计者，并被假借“浴盐”等貌似温和的名称销售，试图逃避法律限制。这些危险的、新近出现的新型滥用药物表现出不同的选择性，以促进DA/NE与5-羟色胺的释放，而DA神经传递的选择性被认为与滥用倾向有关。这项F30应用程序建议进行临床前研究，以检查合成卡西酮“浴盐”产生的与滥用相关的行为和神经化学影响的结构性决定因素。为了评估卡西酮衍生物滥用相关刺激效应的结构决定因素，该应用程序将 关注美卡西酮支架的一个特征：苯环的对位取代基。为了评价甲卡西酮衍生物的物理化学参数(空间体积、亲脂性和给电子/吸电子能力)对体外单胺转运体选择性以及体内神经化学和行为效应的影响，我们将研究一系列新的美卡西酮衍生物。我们假设，对位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-羟色胺的释放(由体内微透析确定)和行为选择性以产生滥用相关效应(由颅内自我刺激(ICSS)确定)。该项目的完成将有助于更好地了解合成卡西尼酮类似物与滥用有关的作用机制，从而能够开发治疗“浴盐”中毒的新策略，并改善与“浴盐”滥用有关的临床结果。

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.