<i>N</i>-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1
<i>N</i>-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1
复制标题
具有高 TRPV1 拮抗活性的 N-甲基酰胺结构 SB366791 衍生物：用于 PET 放射性示踪剂以可视化 TRPV1
DOI：
10.1039/d2md00158f
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发表时间：
2022
影响因子：
4.1
通讯作者：
Doi Hisashi
中科院分区：
文献类型：
--
作者：
Kida Tatsuya;Takahashi Nobuaki;Mori Masayuki X.;Sun Jiacheng H.;Oota Hideto;Nishino Kosuke;Okauchi Takashi;Ochi Yuta;Kano Daisuke;Tateishi Ukihide;Watanabe Yasuyoshi;Cui Yilong;Mori Yasuo;Doi Hisashi
通过修饰具有药物代表性的TRPV1拮抗剂SB366791的结构，合成了瞬时受体电位阳离子通道亚家族V成员1(TRPV1)靶向化合物。为了避免酰胺-亚胺醇的互变异构化，用钙内流实验评价了结构支撑型N-甲基酰胺类化合物(即3-烷氧基取代的N-甲基酰胺类化合物SB366791)，其中细胞在1.0μM辣椒素存在下表达重组的TRPV1。N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide(2)(RLC-TV1004)和N-{3-(3-fluoropropoxy)phenyl}-N-methyl-4-chlorocinnamamide(4)(RLC-TV1006)的拮抗活性分别是SB366791(IC_(50)：3.7μM)的3倍。这些结果将有助于重振SB366791在药物化学应用中的潜力。用3-甲氧基和3-氟烷氧基制备了放射性[11C]甲氧基或[18F]氟烷氧基的活体正电子发射断层扫描(PET)示踪剂。使用11C或18F标记的衍生物，在大鼠身上进行了探索性的PET成像试验。
Transient receptor potential cation channel subfamily V member 1 (TRPV1)-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist. To avoid amide–iminol tautomerization, structurally supported N-methylated amides (i.e., 3-alkoxy-substitued N-meythylamide derivatives of SB366791) were evaluated using a Ca2+ influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. The antagonistic activities of N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide (2) (RLC-TV1004) and N-{3-(3-fluoropropoxy)phenyl}-N-methyl-4-chlorocinnamamide (4) (RLC-TV1006) were found to be approximately three-fold higher (IC50: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC50: 3.7 μM). These results will help reinvigorate the potential of SB366791 in medicinal chemistry applications. The 3-methoxy and 3-fluoroalkoxy substituents were used to obtain radioactive [11C]methoxy- or [18F]fluoroalkoxy-incorporated tracers for in vivo positron emission tomography (PET). Using the 11C- or 18F-labeled derivatives, explorative PET imaging trials were performed in rats.