Halogenated mazindol analogs as potential inhibitors of the cocaine binding site at the dopamine transporter.
Halogenated mazindol analogs as potential inhibitors of the cocaine binding site at the dopamine transporter.
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卤化马吲哚类似物作为多巴胺转运蛋白上可卡因结合位点的潜在抑制剂。
DOI：
10.1021/jm960288w
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Kuhar,MJ
中科院分区：
文献类型：
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作者：
Houlihan,WJ;Boja,JW;Parrino,VA;Kopajtic,TA;Kuhar,MJ
合成了一系列卤代(F，Cl，Br，I)、嘧啶和二氮杂环的马吲哚同系物，并评价了它们取代[3 H]Win 35,428结合和抑制[3 H]多巴胺(DA)在大鼠纹状体组织中摄取的能力。除2‘-氯(6)和2’-溴(16)外，所有化合物均比(R)-可卡因更有效地取代了[~3H]Win的35,428结合，并抑制了[~H]DA的摄取。结构−活性研究表明，咪唑类化合物与游离苯基的3‘-或4’-位含有一个或两个氯或溴原子的化合物对[~3H]Win 35,428结合的抑制效果最好。咪唑环被嘧啶或二氮杂环取代增强了结合抑制。6-(3‘-chlorophenyl)-2，3，4，6-tetrahydropyrimido[2，1-a]isoindol-6-ol(23；IC501.0 nM；8×MAZINDOL)和7-(3‘，4‘-dichlorophenyl)-2，3，4，5-tetrahydro-7H-diazepino[2，1-a]isoindol-7-ol(28；IC500.26 NM；32×MAZINDOL)对[~3H]Win 35,428结合和[~3H]DA摄取的抑制作用最强。结合抑制和摄取抑制之间没有显著差异。Mazindol、24和27对5-羟色胺(5-HT)摄取部位的选择性分别是5-羟色胺(5-HT)摄取的5倍、250倍和465倍，对多种神经递质受体部位的亲和力很弱或没有亲和力。
A series of halogenated (F, Cl, Br, I), pyrimido and diazepino homologs of mazindol were prepared and evaluated for their ability to displace [3H]WIN 35,428 binding and to inhibit uptake of [3H]dopamine (DA) in rat striatal tissue. All of the compounds except for the 2‘-chloro (6) and 2‘-bromo (16) analogs of mazindol displaced [3H]WIN 35,428 binding and inhibited [3H]DA uptake more effectively than (R)-cocaine. Structure−activity studies indicated that best inhibition of [3H]WIN 35,428 binding occurred in the imidazo series with compounds containing one or two Cl or Br atoms in the 3‘- or 4‘-position of the free phenyl group. Replacement of the imidazo ring by a pyrimido or diazepino ring enhanced binding inhibition. The most potent inhibitors of [3H]WIN 35,428 binding and [3H]DA uptake were 6-(3‘-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol (23; IC501.0 nM; 8× mazindol) and 7-(3‘,4‘-dichlorophenyl)-2,3,4,5-tetrahydro-7H-diazepino[2,1-a]isoindol-7-ol (28; IC500.26 nM; 32× mazindol), respectively. No significant differences was found between binding and uptake inhibition. Mazindol and the pyrimido and diazepino homologs24and27showed a selectivity for the DA uptake over the serotonin (5-HT) uptake site of 5-, 250-, and 465-fold, respectively, and displayed weak or no affinity for a variety of neurotransmitter receptor sites.