Weber M, Dietrich D, Gräsel I, Reuter G, Seifert G, Steinhäuser C
Experimental Neurobiology, Neurosurgery, Bonn University, Bonn, Germany Institute of Pharmacy, Jena University, Jena, Germany.
J Neurochem. 2001 May;77(4):1108-15. doi: 10.1046/j.1471-4159.2001.00340.x.
6-Hydroxykynurenic acid (6-HKA), a derivative of kynurenic acid (KYNA) extracted from Ginkgo biloba leaves, was tested for its putative glutamate receptor (GluR) antagonism in comparison to the scaffold substance. The patch-clamp method together with fast-application techniques were used to estimate inhibition by 6-HKA and KYNA of agonist binding at NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (NMDARs and AMPARs) of CA1 pyramidal neurones. 6-Hydroxykynurenic acid proved to be a low-affinity antagonist. When comparing with KYNA, 6-HKA was less potent at NMDARs (IC(50) = 136 versus 59 microM), but showed a higher affinity to AMPARs (K(B) = 22 versus 172 microM). The replacement of 6-HKA and KYNA by glutamate was investigated on outside-out patches. Both antagonists competitively inhibited AMPAR responses and displayed fast unbinding kinetics, but the derivative was significantly slower displaced than KYNA (tau = 1.63 versus 1.22 ms). Our findings demonstrate that 6-hydroxylation considerably changes the pharmacological profile of KYNA. Among the 6-derivatives of KYNA, 6-HKA shows the highest affinity to AMPARS: Despite its relatively low lipophily, these properties might be of clinical relevance under conditions that compromise the integrity of the blood-brain barrier. Furthermore, 6-HKA should be a useful tool to analyse glutamate-mediated synaptic responses.
6-羟基犬尿喹啉酸（6-HKA）是从银杏叶中提取的犬尿喹啉酸（KYNA）的衍生物，与支架物质相比，对其假定的谷氨酸受体（GluR）拮抗作用进行了测试。采用膜片钳技术结合快速给药技术来评估6-HKA和KYNA对CA1锥体神经元NMDA和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体（NMDARs和AMPARs）激动剂结合的抑制作用。6-羟基犬尿喹啉酸被证明是一种低亲和力拮抗剂。与KYNA相比，6-HKA对NMDARs的效力较低（IC(50) = 136 μM对59 μM），但对AMPARs的亲和力较高（K(B) = 22 μM对172 μM）。在外侧向外膜片上研究了用谷氨酸替代6-HKA和KYNA的情况。两种拮抗剂均竞争性抑制AMPAR反应并表现出快速解离动力学，但该衍生物的解离明显比KYNA慢（τ = 1.63 ms对1.22 ms）。我们的研究结果表明，6-羟基化显著改变了KYNA的药理特性。在KYNA的6-衍生物中，6-HKA对AMPARS的亲和力最高：尽管其亲脂性相对较低，但在损害血脑屏障完整性的情况下，这些特性可能具有临床意义。此外，6-HKA应该是分析谷氨酸介导的突触反应的有用工具。
