Systemically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents

We have synthesized D-glucose or D-galactose esters of 7-chlorokynurenic ac id (7ClKynA) as prodrugs to facilitate the transport of 7ClKynA across the blood-brain barrier. Intraperitoneal (i.p.) administration of either 7ClKyn A-D-glucopyranos-6'-ylester (7ClKynA/Glu6) or 7ClKynA-D-glucopyranos-3'-yl ester (7ClKyn4/Glu3) was protective against seizures induced by N-methyl-D- aspartate (NMDA) in mice, with the former drug showing the highest anticonv ulsive activity. Systemic injection of equal amounts of 7ClKynA-D-galactopy ranos-6'-yl ester (7ClKynA/Gal6) or free 7ClKynA did not protect against NM DA seizures. Microdialysis in freely moving rats showed the presence of sig nificant amounts of 7ClKynA/Glu6, as well as of 7ClKynA or KynA, in cortica l perfusates after i.p. injections of 7ClKynA/Glu6. In contrast, only small amounts of 7ClKynA or KynA were detected after i.p. injection of unconjuga ted 7ClKynA. Prodrug metabolism has also been examined in mouse cortical cu ltures containing both neurons and astrocytes. 7ClKynA/Glu6 and 7ClKynA/Gal 6 were rapidly metabolized into 7ClKynA and KynA, whereas 7ClKynA/Glu3 was metabolized with a slower kinetics. As a result of its conversion into 7ClK ynA and KynA, 7ClKynA/Glu6 protected cortical neurons against NMDA toxicity . We conclude that sugar conjugates of 7ClKynA (and perhaps of other excita tory amino acid receptor antagonists) are prodrugs of potential interest in the experimental therapy of epilepsy and acute or chronic neurodegenerativ e disorders. (C) 2000 Published by Elsevier Science B.V. All rights reserve d.