Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of amino, fluoro, hydroxyl, methoxyl, methyl, methylene, and oxo substituents on affinity for the dopamine and serotonin transporters
Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of amino, fluoro, hydroxyl, methoxyl, methyl, methylene, and oxo substituents on affinity for the dopamine and serotonin transporters
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DOI：
10.1021/jm701270n
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发表时间：
2008-05-08
影响因子：
7.3
通讯作者：
Rice, Kenner C.
中科院分区：
文献类型：
--
作者：
Hsin, Ling-Wei;Chang, Li-Te;Rice, Kenner C.
合成了在苯基丙基侧链C2和C3位置具有不同取代基的1-[2-[双（4-氟苯基）甲氧基]乙基]-4-（3-苯基丙基）哌嗪（GBR 12909,1）和1-[2-（二苯基甲氧基）乙基]-4-（3-苯基丙基）哌嗪（GBR 12935,2）的新型衍生物，并对其与多巴胺转运体（DAT）和血清素转运体（SERT）的结合能力进行了评价。在C2系列中，具有孤对电子的s构型取代基显著增强了对DAT的亲和力，而取代基的空间效应则不利于DAT的结合亲和力。在C3系列中，单电子对和取代基的空间效应似乎都不影响DAT的结合亲和力，而sp(2)杂化取代基对DAT的亲和力有不利影响。在该系列中，2-氟取代的(S)-10具有最高的DAT结合亲和力和良好的DAT选择性，而2-氨基取代的(R)-8对DAT和SERT具有基本相同的亲和力。氧化后的16和18对DAT的选择性最好。
Novel derivatives of 1- [2- [bis(4-fluorophenyl)methoxy] ethyl] -4-(3 -phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethy1]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp(2) hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT.