Novel tropane-based irreversible ligands for the dopamine transporter.
Novel tropane-based irreversible ligands for the dopamine transporter.
复制标题
用于多巴胺转运蛋白的新型基于托烷的不可逆配体。
DOI：
10.1021/jm0101904
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发表时间：
2001
影响因子：
7.3
通讯作者：
Newman,AH
中科院分区：
文献类型：
--
作者：
Zou,MF;Kopajtic,T;Katz,JL;Wirtz,S;JusticeJr,JB;Newman,AH
3α-（Diphenylmethoxy）tropane（benztropine）及其类似物是含有托烷环的多巴胺摄取抑制剂，其结合和行为特征与可卡因不同。我们之前制备了一种基于苯托品的光亲和标记物[125 I]-（N-[4-（4 '-叠氮基-3'-碘苯基）丁基]-3α-[双（4 '-氟苯基）甲氧基]托烷，[125 I]1，其共价连接到多巴胺转运蛋白（DAT）的1−2跨膜区。这与由基于可卡因的光亲和标记物[125 I]2（RTI 82）标记的4−7跨膜区形成对比。为了进一步表征这些不同的结合结构域，期望具有从托烷环上的相同位置延伸的4 '-叠氮基-3'-碘苯基取代基的光亲和配体。因此，研究了该取代基与苯并托品系列中的托烷氮之间的最佳烷基连接基的鉴定，以最终制备相同的2的N-取代类似物。在这方面，合成了3α-[双（4 ′-氟苯基）甲氧基]托烷的N-[4-（4 ′-叠氮基-3 ′-碘苯基）丙基]类似物（9a）以及两种不需要光活化就能进行不可逆结合的异硫氰酸酯类似物（10 a，B）。这些目标化合物的合成是通过改进1的合成策略实现的。对这些化合物取代大鼠尾壳核DAT处[3 H]WIN 35 428结合的评价显示，在1中发现的4 '-叠氮基-3'-碘苯基丁基取代基提供了最佳结合亲和力，并被选择取代2上的N-CH 3基团。合成了化合物2的4 ′-叠氮基-3 ′-碘苯基-和4 ′-异硫氰酸基苯基丁基类似物（分别为25和26）。两种产品与DAT结合的效力（IC 50 = 30 nM）与RTI 82（2）相当。此外，化合物26在用hDAT稳定转染的HEK 293细胞中表现出[3 H]WIN 35 428的耐洗置换。这些配体将提供重要的工具，进一步表征结合域托烷为基础的多巴胺摄取抑制剂在DAT。
3α-(Diphenylmethoxy)tropane (benztropine) and its analogues are tropane ring-containing dopamine uptake inhibitors that display binding and behavioral profiles that are distinct from cocaine. We previously prepared a benztropine-based photoaffinity label [125I]-(N-[4-(4‘-azido-3‘-iodophenyl)butyl]-3α-[bis(4‘-fluorophenyl)methoxy]tropane, [125I]1, that covalently attached to the 1−2 transmembrane spanning region of the dopamine transporter (DAT). This was in contrast to the 4−7 transmembrane spanning region labeled by a cocaine-based photoaffinity label, [125I]2(RTI 82). To characterize further these different binding domains, photoaffinity ligands that had the 4‘-azido-3‘-iodophenyl substituent extended from the same position on the tropane ring were desirable. Thus, identification of the optimal alkyl linker between this substituent and the tropane nitrogen in the benztropine series was investigated to ultimately prepare the identical N-substituted analogue of2. In this pursuit, theN-[4-(4‘-azido-3‘-iodophenyl)propyl] analogue of 3α-[bis(4‘-fluorophenyl)methoxy]tropane (9a) was synthesized as well as two isothiocyanate analogues that do not require photoactivation (10a,b) for irreversible binding. The synthesis of these target compounds was achieved using a modification of the strategy developed for1. Evaluation of these compounds for displacing [3H]WIN 35 428 binding at DAT in rat caudate putamen revealed that the 4‘-azido-3‘-iodophenylbutyl substituent, found in1, provided optimal binding affinity and was chosen to replace the N−CH3group on2. Both the 4‘-azido-3‘-iodophenyl- and the 4‘-isothiocyanatophenylbutyl analogues of2(25and26, respectively) were synthesized. Both products bound to DAT with comparable potency (IC50= 30 nM) to RTI 82 (2). In addition, compound26demonstrated wash-resistant displacement of [3H]WIN 35 428 in HEK 293 cells stably transfected with hDAT. These ligands will provide important tools for further characterizing the binding domains for tropane-based dopamine uptake inhibitors at the DAT.