FACILITATED BRAIN UPTAKE OF 4-CHLOROKYNURENINE AND CONVERSION TO 7-CHLOROKYNURENIC ACID

7-CHLOROKYNURENIC acid (7-Cl-KYNA) and 5,7-dichlorokynurenic acid (5,7 -Cl-2-KYNA) are of therapeutic interest as potent glycine/N-methyl-D-a spartate (NMDA) receptor antagonists, but are excluded from brain by t he blood-brain barrier. We examined whether these compounds could be d elivered to brain through their respective precursors, L-4-chlorokynur enine (4-Cl-KYN) and L-4,6-dichlorokynurenine (4,6-Cl-2-KYN), which ar e amino acids. 4-Cl-KYN was shown to be rapidly shuttled into the brai n by the large neutral amino acid transporter of the blood-brain barri er (K-m = 105 +/- 14 mu M, V-max = 16.9 +/- 2.3 nmol min(-1) g(-1)) an d to be converted intracerebrally to 7-Cl-KYNA. 4,6-Cl-2-KYN also expr essed 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 del ivery of glycine-NMDA receptor antagonists.