Expansion of structure-activity studies of piperidine analogues of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) compounds by altering substitutions in the N-benzyl moiety and behavioral pharmacology of selected molecules
Expansion of structure-activity studies of piperidine analogues of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) compounds by altering substitutions in the N-benzyl moiety and behavioral pharmacology of selected molecules
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DOI：
10.1021/jm010316x
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发表时间：
2002-01-31
影响因子：
7.3
通讯作者：
Reith, MEA
中科院分区：
文献类型：
--
作者：
Dutta, AK;Davis, MC;Reith, MEA
合成了多巴胺转运蛋白（DAT）特异性化合物4-[2-（二苯基甲氧基）乙基]-1-苄基哌啶的一系列取代的N-苄基类似物，并进行了生物学表征。不同的4 ′-烷基、4 ′-链烯基和4 ′-炔基取代基被引入苄基部分的苯环中，同时沿着相同的苯环被异构的α-和β-萘基取代。还在3 '-和4'-位引入了不同的极性取代。通过分别与[3 H]WIN 35 428、[H-3]西酞普兰和[H-3]nisoxetine竞争，测试了新化合物在脑中多巴胺、5-羟色胺和去甲肾上腺素转运系统的结合亲和力。还评价了所选化合物抑制[H-3]多巴胺摄取的活性。结合结果表明，在4 '-位的烯基和炔基取代产生有效的化合物，其中具有乙烯基取代的化合物6是最有效的。三种选定化合物的体内评价表明，尽管它们在DAT下具有高效力，但当在相似剂量范围内测试时，这些化合物刺激运动活性（LAM小于可卡因）。在药物辨别研究程序中，这三种化合物中没有一种从训练区分10 mg/kg可卡因和溶剂的小鼠中的可卡因中泛化。在一个4小时的时间过程LMA实验中，我们以前的铅哌啶衍生物（1a）之一，表现出相当长的延长作用。因此，在这份报告中，我们描述了一种新的哌啶类似物的结构-活性关系的研究评估在体外转运蛋白测定和在体内的行为活性测量。
A series of substituted N-benzyl analogues of the dopamine transporter (DAT) specific compound, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine were synthesized and biologically characterized. Different 4'-alkyl, 4'-alkenyl, and 4'-alkynyl substituents were introduced in the phenyl ring of the benzyl moiety along with the replacement of the same phenyl ring by the isomeric alpha- and beta-naphthyl groups. Different polar substitutions at the 3'- and 4'-position were also introduced. Novel compounds were tested for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in the brain by competing for [3H]WIN 35 428, [H-3]citalopram, and [H-3]nisoxetine, respectively. Selected compounds were also evaluated for their activity in inhibiting the uptake of [H-3]dopamine. Binding results demonstrated that alkenyl and alkynyl substitutions at the 4'-position produced potent compounds in which compound 6 with a vinyl substitution was the most potent. In vivo evaluation of three selected compounds indicated that despite their high potency at the DAT, these compounds stimulated locomotor activity (LAM less than cocaine when tested across similar dose ranges. In a drug discrimination study procedure, none of these three compounds generalized from cocaine in mice trained to discriminate 10 mg/kg cocaine from vehicle. In a 4 h time course LMA experiment, one of our previous lead piperidine derivatives (1a) showed considerable prolonged action. Thus, in this report, we describe a structure-activity relationship study of novel piperidine analogues assessed by both in vitro transporter assays and in vivo behavioral activity measurements.