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

合成卡西酮：一类影响 DAT 的新型非法药物

• 批准号: 8458108
• 负责人: LOUIS J DE FELICE
• 金额: $ 48.36万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458108
• 关键词: Accounting; Affect; Agonist; Amphetamines; Animal Model; Animals; Area; Basic Science; Bathing; Behavior; Behavioral; Biophysics; Brain; Cannabis; Cell membrane; Central Nervous System Stimulants; Chemicals; Cocaine; Collaborations; Data; Dopamine; Dopamine Uptake Inhibitors; Dose; Drug Combinations; Drug abuse; Drug effect disorder; Hand; Hospitals; Human; Illicit Drugs; In Vitro; Individual; Isomerism; Knowledge; Lead; Left; Marketing; Measures; Membrane; Methamphetamine; Microdialysis; Modification; Mole the mammal; Molecular; Nucleus Accumbens; Oocytes; Optics; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Procedures; Protein Isoforms; Protocols documentation; Rana; Rattus; Reporting; Research; Research Personnel; Rewards; Risk; Rodent; Rodent Model; Salts; Sampling; Self Administration; Self Stimulation; Serotonin; Signal Transduction; Societies; Speed; Street Drugs; Structure; Structure-Activity Relationship; System; Testing; Time; United States; United States Food and Drug Administration; Variant; analog; base; cathinone; dopamine transporter; drug testing; ecstasy; experience; extracellular; in vivo; inhibitor/antagonist; interest; khat; member; monoamine; monomethylpropion; multidisciplinary; neurochemistry; novel; research study; response; serotonin transporter; stereochemistry; tool; treatment response; uptake; voltage

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.

描述（由适用提供）：该提案的目的是发现进入非法市场的新药的毁灭性影响的基础。使该项目特别有趣的是，这些新药在结构上与众所周知的药物，苯丙胺和甲基苯丙胺（AMPH和METH）相关。新药之一是Cathinone（Khat），这是一种天然存在的 - Amph的酮衍生物〜另一种是甲性甲酮（MCAT），这是一种类似的Meth衍生物。臭名昭著的现代药物，沐浴盐，现在以残酷的效果穿透了我们的社会，由基本的两个衍生物组成 - 酮苯丙胺结构，Mephedrone（Meph）和MDPV。为了给近期发现的森林人，我们认为其中一种沐浴盐（MEPH）类似于甲基苯丙胺，即通过人多巴胺转运蛋白（HDAT）释放多巴胺，而另一个成分（MDPV）则是可卡因，类似于可卡因，呈HDAT阻滞剂。这种可怕的组合很可能解释了医院对浴盐违规行为报告的破坏性影响。新药将继续出现在市场上，而食品药品监督管理局很难跟上非法变体和新颖的虐待。因此，我们的目标之一是编纂 - - 酮苯丙胺（合成的降芯）的结构变化，该变化将预测它们在街上甚至出现之前对化合物的影响，并加快对化合物的社会和科学反应的速度。我们从三个完整的方向进行了这项研究。首先是我们与一名药物化学家的合作，他们将综合铅导管的变化，以帮助理解药物作用背后的重要部分和变化，目前无法获得的光学异构体，以帮助发现潜在的机制。街头药物总是我们也研究的种族，但是研究合成阴茎的右手和左撇子版本以查看哪种形式之间可能的正或负协同作用是很有趣的。其次，我们将研究街头药物和合成变体对电压和化学控制下细胞膜中多巴胺转运蛋白的直接影响。甲基苯丙胺和MCAT刺激转运蛋白的能力有何不同？哪种合成阴茎是兴奋剂（产生表明DA释放的电信号），哪些是阻滞剂（产生抑制信号）？由于所涉及的药物对多巴胺能和血清能系统具有重叠的作用，因此我们还将研究合成阴茎对人血清素转运蛋白的生物物理作用。最后，我们与一位神经药物学家合作，他们将在啮齿动物大脑的区域释放与药物滥用相关的啮齿动物大脑区域的释放，并响应特定的合成阴茎或药物的组合，例如在沐浴盐中。测试药物的滥用潜力也将以啮齿动物的自我管理方案进行测量。我们认为，这种医学化学，膜生物物理学以及神经化学和行为的综合方法有可能影响滥用药物滥用的重要问题对21世纪的基础科学研究和社会的好处。