Synthesis and biological evaluation of 4-fluoroproline and 4-fluoropyrrolidine-2-acetic acid derivatives as new GABA uptake inhibitors.
Preparation for the N-alkylated derivatives of enantiomerically pure (2S)-4-fluoroproline and (2S)-4-fluoropyrrolidine-2-acetic acid is described. The final compounds were evaluated as potential GAT-1 uptake inhibitors via cultured cell lines expressing mouse GAT-1. Compared with their corresponding 4-hydroxy compounds, these derivatives exhibited slight improvement on their inhibitory potency, but still much weaker than their corresponding compounds with no substituents at the C-4 of the pyrrolidine moiety, with the most potent affinity being about 1/15 fold as that of Tiagabine. The drastic decrease of their affinity may arise from sharp reduction of their basicity due to strong inductive effect of the 4-fluorine. However the configuration of the C-4 linking fluorine did not have much influence on their affinity for GAT-1.
Zhuang
Weiping
W
Fujian Institute of Microbiology, No. 25, Jinbu road, Fuzhou 350007, China.
Zhao
Xueqing
X
Zhao
Gang
G
Guo
Lihe
L
Lian
Yunyang
Y
Zhou
Jingming
J
Fang
Dongsheng
D
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D058805:GABA Uptake Inhibitors; D020128:Inhibitory Concentration 50; D051379:Mice; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000085:Acetates; D058805:GABA Uptake Inhibitors; D011759:Pyrrolidines; C431803:fluoro-proline; D005680:gamma-Aminobutyric Acid; D011392:Proline; C032519:pyrrolidine