Department of Pharmacy, Center for Drug Research , Ludwig-Maximilians-University Munich , Butenandtstrasse 5-13 , D-81377 Munich , Germany.
Scientific Core Unit Electrophysiology , Max-Planck-Institut für Psychiatrie , Kraepelinstrasse 2-10 , 80804 Munich , Germany.
J Med Chem. 2018 Jul 26;61(14):6211-6235. doi: 10.1021/acs.jmedchem.8b00629. Epub 2018 Jul 6.
A series of nipecotic acid derivatives with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their ( E)- and ( Z)-form for their functional inhibitory activity at γ-aminobutyric acid transporters subtype 1 (GAT1), the most common γ-aminobutyric acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their ( E)- but distinctive higher inhibitory potency in their ( Z)-form resulting from photoirradiation. For the most efficient photoactivatable nipecotic acid derivative displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 ± 0.05 (pIC) was found for its ( E)-form. which increased by almost two log units up to 6.38 ± 0.04 when irradiated. The effect of this photoswitchable mGAT1 inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.
合成了一系列具有新型偶氮苯基光致开关 N-取代基的烟碱酸衍生物，并对其（E）-和（Z）-两种形式进行了特征描述，以评估其在γ-氨基丁酸转运体 1（GAT1）上的功能抑制活性。GAT1 是中枢神经系统（CNS）中最常见的γ-氨基丁酸（GABA）转运体亚型。这导致了第一个光致开关配体的鉴定，其在（E）-形式下表现出对 GABA 的中等摄取抑制作用，但在光照射下，（Z）-形式下的抑制作用更为显著。对于显示出 N-丁-3-炔-1-基连接基和末端二苯重氮单元的最有效的光活化烟碱酸衍生物，其（E）-形式的抑制效力为 4.65±0.05（pIC），当照射时，其抑制效力增加了近两个对数单位，达到 6.38±0.04。该光致开关 mGAT1 抑制剂的作用也在来自小鼠的急性海马切片的膜片钳记录中得到了评估和证实。
