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

描述（由申请人提供）：本提案的目的是发现新药进入非法市场的破坏性影响的潜在基础。让这个项目特别有趣的是，这些新药在结构上与众所周知的药物安非他命和甲基苯丙胺（AMPH和METH）有关。其中一种新药是卡西酮（khat），一种天然产生的AMPH -酮衍生物；另一种是甲基卡西酮（MCAT），一种类似于冰毒的衍生物。臭名昭著的当代毒品，浴盐，现在以残酷的影响渗透到我们的社会，是由基本的-酮苯丙胺结构的两种附加衍生物，甲氧麻黄酮（MEPH）和MDPV组成的。为了给最近发现的一个先行者，我们认为其中一种浴盐成分（MEPH）类似于冰毒，即通过人类多巴胺转运蛋白（hDAT）释放多巴胺，而另一种成分（MDPV）类似于可卡因，作为hDAT阻滞剂。这种可怕的结合可能很好地解释了医院对浴盐受害者报告的破坏性影响。新药将继续出现在市场上，食品和药物管理局很难跟上非法变种和新滥用的步伐。因此，我们的目标之一是编纂酮类安非他明（合成卡西酮）的结构变异，以预测它们的影响，并在它们出现在街头时，甚至在它们出现之前，加快社会和科学对它们的反应。我们从三个互补的方向进行研究。首先是我们与一位药物化学家的合作，他将合成铅卡西酮的变化，以帮助理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。街头毒品都是外消旋物，我们也研究了这一点，但研究右旋和左旋合成卡西酮更有兴趣，看看哪一种更活跃，并研究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。甲基安非他明和MCAT在刺激转运蛋白的能力上有何不同？哪些合成卡西酮是兴奋剂（产生指示DA释放的电信号），哪些是阻滞剂（产生抑制信号）？由于所讨论的药物对多巴胺能和血清素能系统有重叠作用，我们还将研究合成卡西酮对人体血清素转运体的生物物理作用。最后，我们与一位神经药理学家合作，他将测量啮齿动物大脑中与药物滥用有关的区域多巴胺和血清素的释放，以及对特定合成卡西酮或药物组合（如浴盐）的反应。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测量。我们认为这种结合药物化学、膜生物物理学、神经化学和行为学的方法有可能影响药物滥用的重要问题，从而使21世纪的基础科学研究和社会受益。

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.