Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs

Francesco P. Bonina, Loredana Arenare, Rosa Ippolito, Gianpiero Boatto, Giuseppe Battaglia, Valeria Bruno, Paolo De Caprariis

Research output: Contribution to journalArticle

Abstract

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. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)79-88
Number of pages10
JournalInternational Journal of Pharmaceutics
Volume202
Issue number1-2
DOIs
Publication statusPublished - Jul 20 2000

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Prodrugs
Anticonvulsants
Pharmacokinetics
Esters
Hydrolysis
N-Methylaspartate
Blood-Brain Barrier
Seizures
N-Methyl-D-Aspartate Receptors
Galactose
Glycine
Glucose
Food
7-chlorokynurenic acid
Brain
In Vitro Techniques

Keywords

  • 7-Chlorokynurenic acid
  • Anticonvulsant
  • Blood-brain barrier
  • NMDA-receptor
  • Prodrug

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. / Bonina, Francesco P.; Arenare, Loredana; Ippolito, Rosa; Boatto, Gianpiero; Battaglia, Giuseppe; Bruno, Valeria; De Caprariis, Paolo.

In: International Journal of Pharmaceutics, Vol. 202, No. 1-2, 20.07.2000, p. 79-88.

Research output: Contribution to journalArticle

Bonina, Francesco P. ; Arenare, Loredana ; Ippolito, Rosa ; Boatto, Gianpiero ; Battaglia, Giuseppe ; Bruno, Valeria ; De Caprariis, Paolo. / Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. In: International Journal of Pharmaceutics. 2000 ; Vol. 202, No. 1-2. pp. 79-88.
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