Synthesis and in Vitro Biological Evaluation of Carbonyl Group-Containing Analogues for 蟽1 Receptors

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• 作者：Wei Wang ; Jinquan Cui ; Xiaoxia Lu ; Prashanth K. Padakanti ; Jinbin Xu ; Stanley M. Parsons ; Robert R. Luedtke ; Nigam P. Rath ; Zhude Tu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 11, 2011
• 年：2011
• 卷：54
• 期：15
• 页码：5362-5372
• 全文大小：977K
• 年卷期：v.54,no.15(August 11, 2011)
• ISSN：1520-4804

文摘

To identify the ligands for 蟽₁ receptors that are potent and selective, analogues of prezamicol and trozamicol scaffolds of carbonyl-containing vesicular acetylcholine transporter (VAChT) inhibitors were explored. Of the 23 analogues synthesized and tested, 5 displayed very high affinity for 蟽₁ (K_i = 0.48鈥?.05 nM) and high selectivity for 蟽₁ relative to 蟽₂ receptors (蟽₁/蟽₂ selectivity of >749-fold). Four of the five compounds (14a, 14b, 14c, and 14e) showed very low affinity for VAChT (K_i > 290 nM), and the fifth compound (14g) showed moderate affinity for VAChT (K_i = 44.2 nM). The compound [1鈥?(4-fluorobenzyl)-3鈥?hydroxy[1,4鈥瞉bipiperidinyl-4-yl]-(4-fluorophenyl)methanone (14a) displayed very high affinity and selectivity for 蟽₁ receptor (K_i = 0.48 nM, 蟽₁/蟽₂ > 3600). All four of these most promising compounds (14a, 14b, 14c, and 14e) can be radiosynthesized with fluorine-18 or carbon-11, which will allow further evaluation of their properties as PET probes for imaging 蟽₁ receptor in vivo.