Synthetic cathinones: a new class of illicit drugs affecting DAT & SERT

说明(由申请人提供)：本提案的目的是发现新药物进入非法市场的破坏性影响的根本基础。让该项目特别有趣的是，这些新药在结构上与众所周知的毒品苯丙胺和甲基苯丙胺(安非他明和冰毒)有关。其中一种新药是卡西酮(KHAT)，这是一种自然产生的氨基苯丙酮衍生物。另一种是美卡西酮(MCAT)，它是冰毒的类似衍生物。臭名昭著的当代药物浴盐现在正以残酷的效果渗透到我们的社会中，它由两个额外的基本酮基苯丙胺结构的衍生物组成，即甲氧麻黄酮(Mephedrone)和MDPV。根据最近的一项发现，我们认为其中一个浴盐成分(Meph)是类似冰毒的，即通过人类多巴胺转运体(HDAT)释放多巴胺，而另一个成分(MDPV)是类似可卡因的，充当HDAT阻滞剂。这种可怕的组合很可能解释了医院报告的浴盐受害者的破坏性影响。新药将不会继续出现在市场上，食品和药物管理局很难跟上非法变种和新的滥用。因此，我们的目标之一是编纂酮基苯丙胺(合成卡西酮)的结构变体，以预测它们的影响，并在化合物出现在街道上时，甚至在它们出现之前，加快对它们的社会和科学反应。我们从三个相辅相成的方向来研究这项研究。首先是我们与一位药物化学家的合作，他将合成不同的先导卡西酮，以帮助了解药物作用背后的重要部分和变化，以及目前无法获得的光学异构体，以帮助揭示潜在的机制。街头药物总是外消旋体，我们也对此进行研究，但有兴趣研究合成卡西酮的右旋和左旋版本，以确定哪种更有效，并研究这两种形式之间可能的积极或消极协同作用。其次，我们将研究在电压和化学控制下，街头药物和合成变异体对细胞膜多巴胺转运体的直接影响。冰毒和MCAT在刺激转运蛋白的能力上有何不同？哪些合成卡西酮是刺激剂(产生指示DA释放的电信号)，哪些是阻滞剂(产生抑制信号)？由于这些药物对多巴胺能系统和5-羟色胺能系统有重叠作用，我们还将研究合成卡西酮对人类5-羟色胺转运体的生物物理影响。最后，我们与一位神经药理学家合作，他将测量与药物滥用相关的啮齿动物大脑区域的多巴胺和5-羟色胺的释放，以及对特定的合成卡西酮或药物组合的反应，如浴盐。测试药物的滥用潜力也将在啮齿类动物的自我给药方案中进行衡量。我们认为，这种药物化学、膜生物物理学、神经化学和行为学的结合方法有可能影响药物滥用的重要问题，造福于21世纪的基础科学研究和社会。

DESCRIPTION (provided by applicant): The aim of this proposal is to discover the underlying basis for the devastating effect of new drugs entering the illicit market. What makes the project especially interesting is that these new drugs are structurally related to the well-known drugs, amphetamine and methamphetamine (AMPH and METH). One of the new drugs is cathinone (khat), a naturally occurring ¿-keto derivative of AMPH~ another is methcathinone (MCAT), an analogous derivative of METH. The infamous and contemporary drug, bath salts, now penetrating our society with cruel effect, is composed of two additional derivatives of the basic ¿-keto amphetamine structure, mephedrone (MEPH) and MDPV. To give a forerunner of a recent discovery, we believe that one of the bath salts ingredients (MEPH) is METH-like, i.e., a dopamine releaser via the human dopamine transporter (hDAT), while the other component (MDPV) is cocaine-like, acting as an hDAT blocker. This horrific combination may well account for the devastating effects reported by hospitals for bath salts victims. New drugs will continue t appear on the market, and it is difficult for the Food and Drug Administration to keep up with illegal variants and novel abuses. One of our objectives, therefore, is to codify structural varians of the ¿-keto amphetamines (synthetic cathinones) that will predict their effects and speed societal and scientific responses to compounds as they appear on the street, and even before they appear. We approach this research from three complementary directions. First is our collaboration with a medicinal chemist, who will synthesize variations of the lead cathinones, to help understand important moieties and variations behind drug actions, and presently unavailable optical isomers to help uncover underlying mechanisms. Street drugs are invariably racemates, which we also study, but it is of interest to study right- and left-handed versions of synthetic cathinones to see which is more active and study possible positive or negative synergy between the two forms. Second, we will study the direct effect of street drugs and synthesized variants on the dopamine transporter in cell membranes under voltage and chemical control. How do METH and MCAT differ in their ability to stimulate transporters? Which of the synthetic cathinones are stimulants (producing electrical signals indicative of DA release) and which are blockers (producing inhibitory signals)? Because the drugs in question have overlapping effects on the dopaminergic and serotonergic systems, we will also study the biophysical effects of synthetic cathinones on the human serotonin transporter. Finally, we have teamed up with a neuropharmacologist who will measure the release of dopamine and serotonin in regions of the rodent brain associated with drug abuse and in response to specific synthetic cathinones or combination of drugs, as in bath salts. The abuse potential of test drugs will also be measured in self-administration protocols in rodents. We think this combined approach of medicinal chemistry, membrane biophysics, and neurochemistry and behavior has the potential to impact important problems in drug abuse to the benefit of basic science research and society in the 21st century.