Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [(3)H]dopamine uptake at the vesicular monoamine transporter-2.
Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [(3)H]dopamine uptake at the vesicular monoamine transporter-2.
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DOI：
10.1016/j.bmcl.2016.03.119
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发表时间：
2016-05-15
影响因子：
2.7
通讯作者：
Crooks PA
中科院分区：
文献类型：
--
作者：
Joolakanti SR;Nickell JR;Janganati V;Zheng G;Dwoskin LP;Crooks PA
合成了一系列含有芳香族 4-羟基和 4-(2-氟乙氧基) 取代基的山药烷和 GZ-793A 类似物，并评估了对囊泡单胺转运蛋白 2 (VMAT2) 和多巴胺转运蛋白 (DAT) 的 [3H] 多巴胺 (DA) 摄取的抑制作用，以及对血清素转运蛋白 (SERT) 的 [3H] 血清素摄取的抑制作用。大多数这些化合物在纳摩尔范围内 (Ki = 30–70 nM) 表现出对 VMAT2 的 DA 摄取的有效抑制。两种最有效的类似物 7 和 14 均表现出 31 nM 的 VMAT2 抑制 Ki 值。与山药烷相比，山药烷类似物 14 结合了 4-(2-氟乙氧基) 和 4-羟基芳香族取代基，对 VMAT2 的选择性分别比 DAT 和 SERT 高 96 倍和 335 倍。因此，带有羟基和氟乙氧基部分的山药烷类似物保留了母体化合物对 VMAT2 的高亲和力，同时增强了对 VMAT2 相对于质膜转运蛋白的选择性。
A series of lobelane and GZ-793A analogues that incorporate aromatic 4-hydroxy and 4-(2-fluoroethoxy) substituents were synthesized and evaluated for inhibition of [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [3H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (Ki = 30–70 nM). The two most potent analogues, 7 and 14, both exhibited a Ki value of 31 nM for inhibition of VMAT2. The lobelane analogue 14, incorporating 4-(2-fluoroethoxy) and 4-hydroxy aromatic substituents, exhibited 96- and 335-fold greater selectivity for VMAT2 versus DAT and SERT, respectively, in comparison to lobelane. Thus, lobelane analogues bearing hydroxyl and fluoroethoxy moieties retain the high affinity for VMAT2 of the parent compound, while enhancing selectivity for VMAT2 versus the plasmalemma transporters.