PYROVALERONE ANALOGS: A PROMISING CLASS OF MONOAMINE UPTAKE INHIBITORS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。多巴胺、5-羟色胺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与单胺受体的相互作用的调节对一系列药理学结果具有深远的影响。在寻找治疗可卡因滥用的药物时，我们的兴趣集中在神经递质再摄取机制上。我们描述了一系列2-氨基五苯甲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，但对5-羟色胺转运体几乎没有影响。部分化合物与5HT1a、5HT1b、5HT1C、D1、D2或D3受体无明显亲和力。将先导化合物外消旋1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one，拆分成对映体，发现对映体中生物活性最强的是S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-吡咯烷基-1-基-戊烷-1-酮类似物。讨论：吡喃丙酮类药物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，而且可能比托烷更容易滥用。

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.