Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs.
7-Chlorokynurenic acid 1 is a potent glycine-N-methyl-D-aspartate (NMDA) receptor antagonist, but it shows weak activity after systemic administration. In order to overcome the Blood-brain barrier (BBB), we synthetized three new esters 2-4 of 1 obtained by chemical conjugation with essential nutrients such as glucose and galactose, that are actively transported across the BBB. These compounds were assayed to evaluate their in vitro chemical and enzymatic hydrolysis. In addition the prodrugs 2-4 were tested for their ability to protect mice against NMDA-induced seizures after systemic administration. All the prodrugs 2-4 appeared moderately stable in pH 7.4 buffered solution and were susceptible to in vitro enzymatic hydrolysis. Intraperitoneal administration of either esters 2 or 4 was highly protective against seizures induced by NMDA in mice, with the latter prodrug showing the highest anticonvulsive activity. In addition, ester 4 undergoes a time-dependent extracellular hydrolysis into 1 when applied to mixed cultures of mouse cortical cells, a model that reproduces in vitro the cellular milieu encountered by the prodrugs once they penetrate the brain parenchyma.
Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università di Catania, Viale A. Doria no. 6, 95125, Catania, Italy. boninaf@mbox.unict,it
F P
FP
Bonina
L
L
Arenare
R
R
Ippolito
G
G
Boatto
G
G
Battaglia
V
V
Bruno
P
P
de Caprariis
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002478:Cells, Cultured; D004952:Esters; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000627:therapeutic use*; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D051379:Mice; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D004952:Esters; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011355:Prodrugs; D016202:N-Methylaspartate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid