Carroll F Ivy, Blough Bruce E, Abraham Philip, Mills Andrew C, Holleman J Ashley, Wolckenhauer Scott A, Decker Ann M, Landavazo Antonio, McElroy K Timothy, Navarro Hernán A, Gatch Michael B, Forster Michael J
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA.
J Med Chem. 2009 Nov 12;52(21):6768-81. doi: 10.1021/jm901189z.
A series of bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [(3)H]dopamine ([(3)H]DA), [(3)H]serotonin ([(3)H]5HT), and [(3)H]norepinephrine ([(3)H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [(125)I]RTI-55 in cloned transporters. Several analogues showed increased [(3)H]DA uptake inhibition with reduced or little change in [(3)H]5HT and [(3)H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3-chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction.
合成了一系列安非他酮（1a）类似物（1b - 1ff），并评估了它们的体外和体内药理学特性，目的是开发一种治疗成瘾性方面具有更好特性的1a类似物。通过[³H]多巴胺（[³H]DA）、[³H]5-羟色胺（[³H]5HT）和[³H]去甲肾上腺素（[³H]NE）摄取抑制研究，以及在克隆转运体中使用[¹²⁵I]RTI - 55对多巴胺、5-羟色胺和去甲肾上腺素转运体进行结合研究，来检测它们的体外药理学特性。相对于安非他酮，几种类似物显示出[³H]DA摄取抑制增加，而[³H]5HT和[³H]NE摄取抑制降低或变化很小。在1小时的自发活动观察试验中评估了35种类似物，在8小时的自发活动观察试验中评估了32种类似物，并与可卡因的自发活动进行比较。对24种类似物进行了腹腔注射给药后对可卡因药物辨别泛化的评估，对12种类似物进行了口服给药的可卡因辨别时间过程研究。2-（N-环丙基氨基）-3-氯苯丙酮（1x）在用于治疗可卡因、甲基苯丙胺、尼古丁和其他滥用药物成瘾的间接多巴胺激动剂药物治疗方面具有最有利的体外疗效和体内药理学特征。
