Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2

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• 作者：Shyamsunder R. Joolakanti^a ; ^&dagger ; ; Justin R. Nickell^b ; ^&dagger ; ; Venumadhav Janganati^a ; Guangrong Zheng^a ; Linda P. Dwoskin^b ; Peter A. Crooks^a ; ^{pacrooks@uams.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：4-Hydroxyphenyl lobelane analogues ; Fluorinated lobelane analogues ; Vesicular monoamine transporter-2 ; Dopamine uptake ; Dopamine and serotonin transporter
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：26
• 期：10
• 页码：2422-2427
• 全文大小：1539 K

文摘

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 (K_i = 30–70 nM). The two most potent analogues, 7 and 14, both exhibited a K_i 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.