Journal of Medicinal Chemistry p. 10310 - 10332 (2018)
Update date:2022-08-15
Topics:
Hauke, Tobias J.
Wein, Thomas
H?fner, Georg
Wanner, Klaus T.
This study describes the screening of dynamic combinatorial libraries based on nipecotic acid as core structure with substituents attached to the 5- instead of the common 1-position for the search of novel inhibitors of the GABA transporter GAT1. The generated pseudostatic hydrazone libraries included a total of nearly 900 compounds and were screened for their binding affinities toward GAT1 in competitive mass spectrometry (MS) based Binding Assays. Characterization of the hydrazones with the highest affinities (with cis-configured rac-16gf bearing a 5-(1-naphthyl)furan-2-yl residue and a four atom spacer being the most potent) in binding and uptake experiments revealed an allosteric interaction at GAT1, which was not reported for any other nipecotic acid derivative up to now. Therefore, the herein introduced 5-substituted nipecotic acid derivatives could serve as valuable tools for investigations of allosterically modulated GABA transport mediated by GAT1 and furthermore as starting point for a new class of GAT1 inhibitors.
View MoreContact:86-25-58619180
Address:Nanjing High-Tech Zone 10 Xinghuo Road Pukou District Nanjing, Jiangsu 210061 The People's Republic of China
Contact:0550-7041128 0550-7090578
Address:Wangdian Street,Xinjie Town
TAIZHOU XINGCHENG CHEMPHARM CO.,LTD.
Contact:0086-0576-88551200,88886292 ,88880039
Address:B Area. 10 Floor.Yaodadasha. 289#.Shifu Road.Taizhou.Zhejiang.China
Xiamen Kaijia Imp & Exp Co., Ltd.
Contact:86-592-5101177
Address:Room406 Luhui Building No. 65 Haitian Road Huli Xiamen,China.
Jining Shengrun Chemical Industry Co., Ltd.
Contact:+86-537-7121666 ,
Address:West Ring Road,Wenshang County Shandong Province
Doi:10.1021/jacs.8b02124
(2018)Doi:10.1016/S0040-4039(01)81153-9
(1984)Doi:10.1016/j.bmc.2006.09.008
(2006)Doi:10.1002/ejoc.200600073
(2006)Doi:10.1016/j.bmcl.2006.08.012
(2006)Doi:10.1248/cpb.32.1126
(1984)