Structural determinants of abuse-related effects of synthetic cathinone analogs

描述（由申请人提供）：卡西酮和甲卡西酮分别是安非他命和甲基苯丙胺的ß-酮类类似物，和它们的安非他命类似物一样，卡西酮和甲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）的释放，而不是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（DEA）列为附表1滥用药物。最近，合成卡西酮类似物在欧洲和美国成为滥用的设计药物，并以“浴盐”等看似温和的名称销售，试图逃避法律限制。这些危险的，最近出现的和新的滥用药物在促进DA/NE与5-HT释放方面表现出不同的选择性，并且对DA神经传递的选择性被认为与滥用风险相关。本F30申请提出临床前研究，以检查合成卡西酮“浴盐”产生的滥用相关行为和神经化学效应的结构决定因素。为了评估卡西酮衍生物滥用相关刺激作用的结构决定因素，本应用程序将

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.