PYROVALERONE ANALOGS: A PROMISING CLASS OF MONOAMINE UPTAKE INHIBITORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。多巴胺、血清素和去甲肾上腺素对哺乳动物系统的神经传递至关重要。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多种药理结果具有深远的影响。我们的兴趣集中在神经递质再摄取机制上，以寻找治疗可卡因滥用的药物。我们描述了一系列2-氨基戊烯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，对血清素转运几乎没有影响。一部分化合物对5HT1A、5HT1B、5HT1C、D1、D2或D3受体没有显著的亲和力。外消旋先导化合物1-（4-甲基苯基）-2-吡咯烷-1-基戊烷-1- 1被分解成对映体，其中S异构体是最具生物活性的对映体。在这些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-基戊烷-1- 1类似物。讨论：焦戊酮的治疗潜力值得考虑，因为它们不同于可卡因的tropane类似物，并且可能比tropane具有更少的滥用风险。

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.