Synthesis, Characterization, and Metabolism Studies of Fluspidine Enantiomers
Synthesis, Characterization, and Metabolism Studies of Fluspidine Enantiomers
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DOI：
10.1002/cmdc.201300322
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发表时间：
2013-12-01
期刊：
影响因子：
3.4
通讯作者：
Wuensch, Bernhard
中科院分区：
文献类型：
--
作者：
Holl, Katharina;Falck, Evamaria;Wuensch, Bernhard
使用手性制备型 HPLC 制备有效 sigma(1) 配体 Fluspidine (1) 的对映体。合成外消旋甲苯磺酸酯 2 并随后分离对映体，得到对映体纯度极佳的 (R)-2 和 (S)-2。由(R)-2和(S)-2通过四正丁基氟化铵亲核取代合成了氟吡啶对映体(R)-1和(S)-1，得到(R)-1和(S)-1，分别为99.6%ee和96.4%ee。甲苯磺酸酯(R)-2和(S)-2还可作为放射合成对映体纯放射性示踪剂[F-18](R)-1和[F-18](S)-1的前体。通过将纯对映体的圆二色光谱与简化模型化合物的计算圆二色光谱进行比较，阐明了纯对映体的绝对构型。在受体结合研究中，两种对映体均表现出非常高的 sigma(1) 受体亲和力和对 sigma(2) 受体的选择性。 (R)-Fluspidine ((R)-1) 是优异构体，K-i 值为 0.57nM，愉悦比为 4。将 (R)-1 和 (S)-1 与大鼠肝微粒体一起孵育，分别鉴定出 7 种和 8 种代谢物。尽管S构型对映体形成了额外的代谢物(S)-1-3，但它比(R)-1在代谢上更稳定。
The enantiomers of the potent sigma(1) ligand fluspidine (1) were prepared by using chiral preparative HPLC. Synthesis of racemic tosylate 2 and subsequent separation of enantiomers yielded (R)-2 and (S)-2 in excellent enantiomeric purities. The fluspidine enantiomers (R)-1 and (S)-1 were synthesized from (R)-2 and (S)-2 by nucleophilic substitution with tetra-n-butylammonium fluoride, affording (R)-1 with 99.6%ee and (S)-1 with 96.4%ee. Tosylates (R)-2 and (S)-2 can also serve as precursors for the radiosynthesis of enantiomerically pure radiotracers [F-18](R)-1 and [F-18](S)-1. The absolute configuration of the pure enantiomers was elucidated by comparison of their CD spectra with a calculated CD spectrum of a simplified model compound. In receptor binding studies, both enantiomers displayed very high sigma(1) receptor affinity and selectivity against the sigma(2) receptor. (R)-Fluspidine ((R)-1) is the eutomer, with a K-i value of 0.57nM and a eudysmic ratio of 4. Incubation of (R)-1 and (S)-1 with rat liver microsomes led to the identification of seven and eight metabolites, respectively. Although the S-configured enantiomer formed additional metabolite (S)-1-3, it is metabolically more stable than (R)-1.