Joolakanti Shyamsunder R, Nickell Justin R, Janganati Venumadhav, Zheng Guangrong, Dwoskin Linda P, Crooks Peter A
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Bioorg Med Chem Lett. 2016 May 15;26(10):2422-2427. doi: 10.1016/j.bmcl.2016.03.119. Epub 2016 Apr 1.
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 [(3)H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [(3)H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (Ki=30-70nM). The two most potent analogues, 7 and 14, both exhibited a Ki value of 31nM 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.
合成了一系列含有芳香族4-羟基和4-(2-氟乙氧基)取代基的洛贝林和GZ-793A类似物，并评估了它们对囊泡单胺转运体-2（VMAT2）和多巴胺转运体（DAT）的[(3)H]多巴胺（DA）摄取以及对5-羟色胺转运体（SERT）的[(3)H]5-羟色胺摄取的抑制作用。这些化合物中的大多数在纳摩尔范围内对VMAT2的DA摄取表现出强效抑制（Ki = 30 - 70 nM）。两种最有效的类似物7和14，对VMAT2抑制的Ki值均为31 nM。与洛贝林相比，含有4-(2-氟乙氧基)和4-羟基芳香取代基的洛贝林类似物14对VMAT2相对于DAT和SERT的选择性分别高96倍和335倍。因此，带有羟基和氟乙氧基部分的洛贝林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相对于质膜转运体的选择性。
