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.