title: Systemically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents.
abstract: We have synthesized D-glucose or D-galactose esters of 7-chlorokynurenic acid (7ClKynA) as prodrugs to facilitate the transport of 7ClKynA across the blood-brain barrier. Intraperitoneal (i.p.) administration of either 7ClKynA-D-glucopyranos-6'-ylester (7ClKynA/Glu6) or 7ClKynA-D-glucopyranos-3'-yl ester (7ClKynA/Glu3) was protective against seizures induced by N-methyl-D-aspartate (NMDA) in mice, with the former drug showing the highest anticonvulsive activity. Systemic injection of equal amounts of 7ClKynA-D-galactopyranos-6'-yl ester (7ClKynA/Gal6) or free 7ClKynA did not protect against NMDA seizures. Microdialysis in freely moving rats showed the presence of significant amounts of 7ClKynA/Glu6, as well as of 7ClKynA or KynA, in cortical perfusates after i.p. injections of 7ClKynA/Glu6. In contrast, only small amounts of 7ClKynA or KynA were detected after i.p. injection of unconjugated 7ClKynA. Prodrug metabolism has also been examined in mouse cortical cultures containing both neurons and astrocytes. 7ClKynA/Glu6 and 7ClKynA/Gal6 were rapidly metabolized into 7ClKynA and KynA, whereas 7ClKynA/Glu3 was metabolized with a slower kinetics. As a result of its conversion into 7ClKynA and KynA, 7ClKynA/Glu6 protected cortical neurons against NMDA toxicity. We conclude that sugar conjugates of 7ClKynA (and perhaps of other excitatory amino acid receptor antagonists) are prodrugs of potential interest in the experimental therapy of epilepsy and acute or chronic neurodegenerative disorders.
authors.affiliation: I.N.M. Neuromed, Pozilli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: M
authors.initials: M
authors.lastname: La Russa
authors.forename: V
authors.initials: V
authors.lastname: Bruno
authors.forename: L
authors.initials: L
authors.lastname: Arenare
authors.forename: R
authors.initials: R
authors.lastname: Ippolito
authors.forename: A
authors.initials: A
authors.lastname: Copani
authors.forename: F
authors.initials: F
authors.lastname: Bonina
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects; D001711:Biotransformation; D001812:Blood-Brain Barrier; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D017077:Culture Media, Conditioned; D004828:Epilepsies, Partial / Q000139:chemically induced / Q000188:drug therapy*; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005690:Galactose / Q000737:chemistry; D005947:Glucose / Q000737:chemistry*; D007274:Injections, Intraperitoneal; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D017551:Microdialysis; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D017077:Culture Media, Conditioned; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011355:Prodrugs; D016202:N-Methylaspartate; D007736:Kynurenic Acid; D005947:Glucose; C057013:7-chlorokynurenic acid; D005690:Galactose