title: Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid.
abstract: 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.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892-1582, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hokari
authors.forename: H Q
authors.initials: HQ
authors.lastname: Wu
authors.forename: R
authors.initials: R
authors.lastname: Schwarcz
authors.forename: Q R
authors.initials: QR
authors.lastname: Smith
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D010477:Perfusion; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C105630:4,6-dichlorokynurenine; D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D011355:Prodrugs; D007737:Kynurenine; C027883:4-chlorokynurenine; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid