PYROVALERONE ANALOGS: A PROMISING CLASS OF MONOAMINE UPTAKE INHIBITORS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。多巴胺、血清素和去甲肾上腺素是哺乳动物系统中神经传递所必需的。这三种神经递质一直是大量研究的焦点，因为它们的产生及其在单胺受体上的相互作用的调节对许多药理学结果具有深远的影响。我们的兴趣集中在神经递质的再摄取机制在寻找药物滥用可卡因。我们描述了一系列2-氨基戊酮的合成和生物学评价。结果：该阵列产生了多巴胺和去甲肾上腺素转运体的选择性抑制剂，对5-羟色胺转运的影响很小。化合物的子集对5 HT 1A、5 HT 1B、5 HT 1C、D1、D2或D3受体没有显著的亲和力。将先导化合物外消旋1-（4-甲基苯基）-2-吡咯烷-1-基-戊-1-酮拆分成其对映异构体，发现S异构体是最具生物活性的对映异构体。这些DAT/NET选择性化合物中最有效的是1-（3，4-二氯苯基）-和1-萘基-2-吡咯烷-1-基-戊-1-酮类似物。讨论内容：吡咯戊酮的治疗潜力值得考虑，因为它们不同于可卡因的托烷类似物，并且可能比托烷产生更少的滥用倾向。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dopamine, serotonin, and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research because the modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. We describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. Result: This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin transport. A subset of compounds had no significant affinity at 5HT1A, 5HT1B, 5HT1C, D1, D2, or D3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4-dichlorophenyl)- and the 1-naphthyl- 2-pyrrolidin-1-yl-pentan-1-one analogues. Discussion: The therapeutic potential of pyrovalerones merit consideration, as they differ from tropane analogs of cocaine, and may confer less abuse liability than the tropanes.