Madras B K, Reith M E, Meltzer P C, Dutta A K
Department of Psychiatry, Harvard Medical School, Southborough, MA.
Eur J Pharmacol. 1994 Apr 15;267(2):167-73. doi: 10.1016/0922-4106(94)90168-6.
1,4-Disubstituted piperazines such as GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine) and GBR 12935 (1-[2-(bis(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine) are among the most potent and selective ligands for the dopamine transporter in brain. However, they also bind to a widely distributed "piperazine acceptor site". In order to assess whether the piperazine moiety of GBR 12909 is critical for binding to the dopamine transporter, two piperidine analogs of GBR 12909, one with the nitrogen proximal to the diphenylmethyloxy moiety (O-549, (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperidine), the other distal to this moiety (O-526, 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1- (3-phenylpropyl)piperidine) were synthesized. The affinities of O-526, O-549 and GBR 12909 for the dopamine and serotonin transporters in monkey caudate-putamen (Macaca fascicularis) were evaluated using [3H]WIN 35,428 ([3H]CFT, 2 beta-carbomethoxy-3 beta-4-(fluorophenyl)tropane) or [3H]GBR 12935 and [3H]citalopram to label the dopamine and serotonin transporters, respectively. O-526 inhibited [3H]WIN 35,428 binding with potencies that were similar to GBR 12909 (IC50: 24.9 +/- 3.23 vs. 22.0 +/- 2.2 nM, respectively) whereas O-549 was 24 times less potent than O-526 (IC50: 595 +/- 148 nM). The selectivity of GBR 12909 for the dopamine over the serotonin transporter was retained by O-526 but not by O-549 which was relatively non-selective. These results indicate that only one of the two nitrogens on the basic GBR structure is needed for high affinity binding to the dopamine transporter.(ABSTRACT TRUNCATED AT 250 WORDS)
1,4 - 二取代哌嗪，如GBR 12909（1 - [2 - [双（4 - 氟苯基）甲氧基]乙基] - 4 - （3 - 苯基丙基）哌嗪）和GBR 12935（1 - [2 - （双苯基）甲氧基]乙基] - 4 - （3 - 苯基丙基）哌嗪）是脑中多巴胺转运体最有效和选择性最强的配体之一。然而，它们也与广泛分布的“哌嗪受体位点”结合。为了评估GBR 12909的哌嗪部分对与多巴胺转运体结合是否至关重要，合成了GBR 12909的两种哌啶类似物，一种氮原子靠近二苯甲氧基部分（O - 549，（1 - [2 - [双（4 - 氟苯基）甲氧基]乙基] - 4 - （3 - 苯基丙基）哌啶），另一种氮原子远离该部分（O - 526，4 - [2 - [双（4 - 氟苯基）甲氧基]乙基] - 1 - （3 - 苯基丙基）哌啶）。使用[³H]WIN 35,428（[³H]CFT，2β - 甲氧羰基 - 3β - 4 - （氟苯基）托烷）或[³H]GBR 12935和[³H]西酞普兰分别标记多巴胺和5 - 羟色胺转运体，评估了O - 526、O - 549和GBR 12909对猕猴尾状核 - 壳核（食蟹猴）中多巴胺和5 - 羟色胺转运体的亲和力。O - 526抑制[³H]WIN 35,428结合的效力与GBR 12909相似（IC50分别为24.9±3.23对22.0±2.2 nM），而O - 549的效力比O - 526低24倍（IC50：595±148 nM）。O - 526保留了GBR 12909对多巴胺转运体相对于5 - 羟色胺转运体的选择性，而O - 549则相对非选择性。这些结果表明，GBR基本结构上的两个氮原子中只有一个是与多巴胺转运体高亲和力结合所必需的。（摘要截短于250字）
