Synthesis and in Vitro Biological Evaluation of Carbonyl Group-Containing Inhibitors of Vesicular Acetylcholine Transporter

详细信息    查看全文

• 作者：Simon M. N. Efange ; Anil B. Khare ; Krystyna von Hohenberg ; Robert H. Mach ; Stanley M. Parsons ; Zhude Tu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 8, 2010
• 年：2010
• 卷：53
• 期：7
• 页码：2825-2835
• 全文大小：880K
• 年卷期：v.53,no.7(April 8, 2010)
• ISSN：1520-4804

文摘

To identify selective high-affinity inhibitors of the vesicular acetylcholine transporter (VAChT), we have interposed a carbonyl group between the phenyl and piperidyl groups of the prototypical VAChT ligand vesamicol and its more potent analogues benzovesamicol and 5-aminobenzovesamicol. Of 33 compounds synthesized and tested, 6 display very high affinity for VAChT (Kb>ib>, 0.25−0.66 nM) and greater than 500-fold selectivity for VAChT over σb>1b> and σb>2b> receptors. Twelve compounds have high affinity (Kb>ib>, 1.0−10 nM) and good selectivity for VAChT. Furthermore, 3 halogenated compounds, namely, trans-3-[4-(4-fluorobenzoyl)piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (<b>28bb>) (Kb>ib> = 2.7 nM, VAChT/sigma selectivity index = 70), trans-3-[4-(5-iodothienylcarbonyl)piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (<b>28hb>) (Kb>ib> = 0.66 nM, VAChT/sigma selectivity index = 294), and 5-amino-3-[4-(p-fluorobenzoyl)piperidinyl]-2-hydroxy-1,2,3,4,-tetrahydronaphthalene (<b>30bb>) (Kb>ib> = 2.40 nM, VAChT/sigma selectivity index = 410) display moderate to high selectivity for VAChT. These three compounds can be synthesized with the corresponding radioisotopes so as to serve as PET/SPECT probes for imaging the VAChT in vivo.