Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.
Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.
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苏型哌甲酯的叠氮基碘-N-苄基衍生物（利他林，Concerta）：合理设计、合成、药理学评价和多巴胺转运蛋白光亲和标记。
DOI：
10.1016/j.bmc.2010.11.002
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发表时间：
2011
影响因子：
3.5
通讯作者：
Deutsch,HowardM
中科院分区：
文献类型：
--
作者：
Lapinsky,DavidJ;Velagaleti,Ranganadh;Yarravarapu,Nageswari;Liu,Yi;Huang,Yurong;Surratt,ChristopherK;Lever,JohnR;Foster,JamesD;Acharya,Rejwi;Vaughan,RoxanneA;Deutsch,HowardM
与苯托品和可卡因等基于托烷的化合物相比，多巴胺转运体(DAT)的非托烷基光亲和配体相对来说还没有被探索过。为了解决这一知识空白，合成了3-和4-碘代哌酸甲酯的哌啶氮被含光活性叠氮的苄基取代的配体。类似物(±)-3a表现出适度的DAT亲和力，并且放射性碘化版本被证明与培养细胞中表达的大鼠纹状体DAT和HDAT共价结合。(±)-3a与非放射性d-(+)-哌酸甲酯或(−)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane(β-CFT，Win-35,428，一种可卡因类似物)共同孵育可阻断DAT标记。化合物(±)-3a代表了第一个成功的基于哌醋甲酯支架的DAT光亲和配体的例子。这类配体有望帮助定位质膜单胺转运蛋白中的非托烷配体结合口袋。
In contrast to tropane-based compounds such as benztropine and cocaine, non-tropane-based photoaffinity ligands for the dopamine transporter (DAT) are relatively unexplored. Towards addressing this knowledge gap, ligands were synthesized in which the piperidine nitrogen of 3- and 4-iodomethylphenidate was substituted with a benzyl group bearing a photoreactive azide. Analog (±)-3a demonstrated modest DAT affinity and a radioiodinated version was shown to bind covalently to rat striatal DAT and hDAT expressed in cultured cells. Co-incubation of (±)-3a with nonradioactive d-(+)-methylphenidate or (−)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (β-CFT, WIN-35,428, a cocaine analog) blocked DAT labeling. Compound (±)-3a represents the first successful example of a DAT photoaffinity ligand based on the methylphenidate scaffold. Such ligands are expected to assist in mapping non-tropane ligand-binding pockets within plasma membrane monoamine transporters.