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 language | English |
|---|---|
| Pages (from-to) | 79-88 |
| Number of pages | 10 |
| Journal | International Journal of Pharmaceutics |
| Volume | 202 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - Jul 20 2000 |
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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 journal › Article
}
TY - JOUR
T1 - Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs
AU - Bonina, Francesco P.
AU - Arenare, Loredana
AU - Ippolito, Rosa
AU - Boatto, Gianpiero
AU - Battaglia, Giuseppe
AU - Bruno, Valeria
AU - De Caprariis, Paolo
PY - 2000/7/20
Y1 - 2000/7/20
N2 - 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.
AB - 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.
KW - 7-Chlorokynurenic acid
KW - Anticonvulsant
KW - Blood-brain barrier
KW - NMDA-receptor
KW - Prodrug
UR - http://www.scopus.com/inward/record.url?scp=0034691811&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034691811&partnerID=8YFLogxK
U2 - 10.1016/S0378-5173(00)00421-X
DO - 10.1016/S0378-5173(00)00421-X
M3 - Article
C2 - 10915929
AN - SCOPUS:0034691811
VL - 202
SP - 79
EP - 88
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
IS - 1-2
ER -