A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) and 1-¿2-[bis(4-fluorophenyl)methoxy]ethyl¿-4-(3-phenylpropyl)piperazine (3) (GBR 12935 and GBR 12909, respectively), in which the piperazine moiety was replaced by bridged piperazines for structural rigidity, has been designed, synthesized, and evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of (3)H-labeled dopamine (DA). The binding data indicated that compounds 7 and 11, the N-methyl- and N-propylphenyl-3,8-diaza[3.2. 1]bicyclooctane analogues of 3, showed high affinity for the DAT (IC(50) = 8.0 and 8.2 nM, respectively), and 7 had high selectivity at the DAT relative to the serotonin transporter (SERT) (88- and 93-fold for binding and reuptake, respectively). They also displayed linear activity in DA uptake inhibition, possessing a similar binding and reuptake inhibition profile to 3. The N-indolylmethyl analogue 16 showed the highest affinity (IC(50) = 1.4 nM) of the series, with a 6-fold increase over its corresponding N-phenypropyl derivative 11. Interestingly, this compound exhibited a high ratio (29-fold) of IC(50) for the inhibition of DA reuptake versus binding to the DAT. Replacing the piperazine moiety of 2 and 3 with (1S, 4S)-2,5-diazabicyclo[2.2.1]heptane resulted in compounds 23-26, which showed moderate to poor affinity (IC(50) = 127-1170 nM) for the DAT. Substitution of the homopiperazine moiety of 4 with a more rigid 3,9-diazabicyclo[4.2.1]nonane gave compounds 28-33. However, the binding data showed that compound 32 displayed a 10-fold decrease in affinity at the DAT and a 100-fold decrease in selectivity at the DAT relative to the SERT compared to its corresponding homopiperazine compound 4.

中文翻译：

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1- [2- [双[4-（氟苯基）甲氧基]乙基] -4-（3-苯基丙基）哌嗪的桥连哌嗪类似物的合成和转运体结合性质（GBR 12909）。

与1- [2-（二苯基甲氧基）乙基] -4-（3-苯基丙基）哌嗪（2）和1- [2- [双（4-氟苯基）甲氧基]乙基] -4-（3）有关的一系列类似物-苯基丙基）哌嗪（3）（分别为GBR 12935和GBR 12909），其中哌嗪部分被桥连哌嗪取代以提高结构刚性，已经设计，合成并评估了它们与多巴胺转运蛋白（DAT）结合的能力）并抑制（3）H标记的多巴胺（DA）的摄取。结合数据表明，化合物7和11为N-甲基苯基和N-丙基苯基-3,8-二氮杂[3.2。1] 3的双环辛烷类似物，对DAT的亲和力高（分别为IC（50）= 8.0和8.2 nM），相对于血清素转运蛋白（SERT），7对DAT的选择性高（88和93倍）分别用于结合和再摄取）。他们还在DA摄取抑制中显示线性活性，具有与3相似的结合和重摄取抑制曲线。N-吲哚甲基类似物16显示了该系列中最高的亲和力（IC（50）= 1.4 nM），增加了6倍。有趣的是，该化合物在抑制DA再摄取与结合DAT方面表现出高比例（29倍）的IC（50）。用（1S，4S）-2,5-二氮杂双环[2.2.1]庚烷取代2和3的哌嗪部分会产生化合物23-26，其亲和力中等至较差（IC（50）= 127-1170 nM） DAT。用更刚性的3，9-二氮杂双环[4.2.1]壬烷取代4的高哌嗪部分，得到化合物28-33。然而，