Hokari M, Wu H Q, Schwarcz R, Smith Q R
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892-1582, USA.
Neuroreport. 1996 Dec 20;8(1):15-8. doi: 10.1097/00001756-199612200-00004.
7-Chlorokynurenic acid (7-Cl-KYNA) and 5,7-dichlorokynurenic acid (5,7-Cl2-KYNA) are of therapeutic interest as potent glycine/N-methyl-D-aspartate NMDA) receptor antagonists, but are excluded from brain by the blood-brain barrier. We examined whether these compounds could be delivered to brain through their respective precursors, L-4-chlorokynurenine (4-Cl-KYN) and L-4,6-dichlorokynurenine (4,6-Cl2-KYN), which are amino acids. 4-Cl-KYN was shown to be rapidly shuttled into the brain by the large neutral amino acid transporter of the blood-brain barrier (K(m) = 105 +/- 14 microM, Vmax = 16.9 +/- 2.3 nmol min-1 g-1) and to be converted intracerebrally to 7-Cl-KYNA. 4,6-Cl2-KYN also expressed affinity for the transporter, but four-fold less than that of 4-Cl-KYN. In summary, the results show that because of their facilitated uptake 4-Cl-KYN and 4,6-Cl2KYN might be useful prodrugs for brain delivery of glycine-NMDA receptor antagonists.
7-氯犬尿喹啉酸（7-Cl-KYNA）和5,7-二氯犬尿喹啉酸（5,7-Cl2-KYNA）作为有效的甘氨酸/N-甲基-D-天冬氨酸（NMDA）受体拮抗剂具有治疗意义，但被血脑屏障排除在脑外。我们研究了这些化合物是否可以通过它们各自的前体L-4-氯犬尿氨酸（4-Cl-KYN）和L-4,6-二氯犬尿氨酸（4,6-Cl2-KYN）（它们都是氨基酸）递送至脑内。结果表明，4-Cl-KYN可通过血脑屏障的大中性氨基酸转运体快速转运至脑内（米氏常数K(m)=105±14微摩尔，最大反应速度Vmax=16.9±2.3纳摩尔·分钟-1·克-1），并在脑内转化为7-Cl-KYNA。4,6-Cl2-KYN对该转运体也表现出亲和力，但比4-Cl-KYN低四倍。总之，结果表明，由于4-Cl-KYN和4,6-Cl2-KYN的摄取较为容易，它们可能是用于将甘氨酸-NMDA受体拮抗剂递送至脑内的有用前体药物。
