1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogues: A promising class of monoamine uptake inhibitors
1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogues: A promising class of monoamine uptake inhibitors
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DOI：
10.1021/jm050797a
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发表时间：
2006-02-23
影响因子：
7.3
通讯作者：
Madras, BK
中科院分区：
文献类型：
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作者：
Meltzer, PC;Butler, D;Madras, BK
多巴胺、血清素和去甲肾上腺素对于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与单胺受体的相互作用的调节对多种药理学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。在此，我们描述了一系列 2-氨基戊苯酮的合成和生物学评价。该阵列产生了多巴胺和去甲肾上腺素转运蛋白的选择性抑制剂，对血清素运输影响很小。一部分化合物对 5HT(1A)、5HT(1B)、5HT(1C)、D-1、D-2 或 D-3 受体没有显着的亲和力。先导化合物，外消旋1-(4-甲基苯基)-2-吡咯烷-1-基-戊-1-酮4a，被拆分成其对映体，并且发现S异构体是最具生物活性的对映体。这些 DAT/NET 选择性化合物中最有效的是 1-(3,4-二氯苯基)-(4u) 和 1-萘基-(4t) 2-吡咯烷-1-基-戊-1-酮类似物。
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. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT(1A), 5HT(1B), 5HT(1C), D-1, D-2, or D-3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, 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)- (4u) and the 1-naphthyl- (4t) 2-pyrrolidin-1-yl-pentan-1-one analogues.