N-Valproyl-L-Phenylalanine as New Potential Antiepileptic Drug: Synthesis, Characterization and In Vitro Studies on Stability, Toxicity and Anticonvulsant Efficacy

Risultato della ricerca: Article

6 Citazioni (Scopus)

Abstract

Valproic acid (VPA) is considered first-line treatment for primarily generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, MS, 13C and 1H- NMR analyses. The Log DpH7.4 value (0.19) indicated that new molecule was potentially able to cross biological membranes. The resistance to chemical and enzymatic hydrolysis of N-valproyl-L-phenylalanine was also assessed. All trials suggested that the compound, at the pH conditions of the entire gastro-intestinal tract, remained unmodified. Furthermore, the new compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h.The toxicity assay on primary cultures of astrocytes indicated that the synthetized conjugate was less toxic than both free VPA and L-Phenylalanine. In this paper, the anticonvulsant activity of the new compound against epileptic burst discharges evoked in vitro in rat hippocampal slices was also evaluated.These preliminary results underline that N-valproyl-L-phenylalanine as new potential antiepileptic agent could represent a good candidate to further investigations.
Lingua originaleEnglish
pagine (da-a)30-40
Numero di pagine11
RivistaMedicinal Chemistry
Volume11
Stato di pubblicazionePublished - 2015

Fingerprint

Valproic Acid
Anticonvulsants
Seizures
Infantile Spasms
Poisons
In Vitro Techniques
N-valproylphenylalanine
Migraine Disorders
Phenylalanine
Bipolar Disorder
Astrocytes
Epilepsy
Hydrolysis
Membranes
Liver

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Cita questo

@article{d5936b2247df41d88a98736da44c6d8c,
title = "N-Valproyl-L-Phenylalanine as New Potential Antiepileptic Drug: Synthesis, Characterization and In Vitro Studies on Stability, Toxicity and Anticonvulsant Efficacy",
abstract = "Valproic acid (VPA) is considered first-line treatment for primarily generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, MS, 13C and 1H- NMR analyses. The Log DpH7.4 value (0.19) indicated that new molecule was potentially able to cross biological membranes. The resistance to chemical and enzymatic hydrolysis of N-valproyl-L-phenylalanine was also assessed. All trials suggested that the compound, at the pH conditions of the entire gastro-intestinal tract, remained unmodified. Furthermore, the new compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h.The toxicity assay on primary cultures of astrocytes indicated that the synthetized conjugate was less toxic than both free VPA and L-Phenylalanine. In this paper, the anticonvulsant activity of the new compound against epileptic burst discharges evoked in vitro in rat hippocampal slices was also evaluated.These preliminary results underline that N-valproyl-L-phenylalanine as new potential antiepileptic agent could represent a good candidate to further investigations.",
author = "Sutera, {Flavia Maria} and Gabriella Schiera and Giuseppe Avellone and {De Caro}, Viviana and Valerio Rizzo and Giannola, {Libero Italo} and Scaturro, {Anna Lisa} and Fabio Carletti and Pierangelo Sardo and Maria Carafa",
year = "2015",
language = "English",
volume = "11",
pages = "30--40",
journal = "Medicinal Chemistry",
issn = "1573-4064",
publisher = "Bentham Science Publishers B.V.",

}

TY - JOUR

T1 - N-Valproyl-L-Phenylalanine as New Potential Antiepileptic Drug: Synthesis, Characterization and In Vitro Studies on Stability, Toxicity and Anticonvulsant Efficacy

AU - Sutera, Flavia Maria

AU - Schiera, Gabriella

AU - Avellone, Giuseppe

AU - De Caro, Viviana

AU - Rizzo, Valerio

AU - Giannola, Libero Italo

AU - Scaturro, Anna Lisa

AU - Carletti, Fabio

AU - Sardo, Pierangelo

AU - Carafa, Maria

PY - 2015

Y1 - 2015

N2 - Valproic acid (VPA) is considered first-line treatment for primarily generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, MS, 13C and 1H- NMR analyses. The Log DpH7.4 value (0.19) indicated that new molecule was potentially able to cross biological membranes. The resistance to chemical and enzymatic hydrolysis of N-valproyl-L-phenylalanine was also assessed. All trials suggested that the compound, at the pH conditions of the entire gastro-intestinal tract, remained unmodified. Furthermore, the new compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h.The toxicity assay on primary cultures of astrocytes indicated that the synthetized conjugate was less toxic than both free VPA and L-Phenylalanine. In this paper, the anticonvulsant activity of the new compound against epileptic burst discharges evoked in vitro in rat hippocampal slices was also evaluated.These preliminary results underline that N-valproyl-L-phenylalanine as new potential antiepileptic agent could represent a good candidate to further investigations.

AB - Valproic acid (VPA) is considered first-line treatment for primarily generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, MS, 13C and 1H- NMR analyses. The Log DpH7.4 value (0.19) indicated that new molecule was potentially able to cross biological membranes. The resistance to chemical and enzymatic hydrolysis of N-valproyl-L-phenylalanine was also assessed. All trials suggested that the compound, at the pH conditions of the entire gastro-intestinal tract, remained unmodified. Furthermore, the new compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h.The toxicity assay on primary cultures of astrocytes indicated that the synthetized conjugate was less toxic than both free VPA and L-Phenylalanine. In this paper, the anticonvulsant activity of the new compound against epileptic burst discharges evoked in vitro in rat hippocampal slices was also evaluated.These preliminary results underline that N-valproyl-L-phenylalanine as new potential antiepileptic agent could represent a good candidate to further investigations.

UR - http://hdl.handle.net/10447/98563

UR - http://benthamscience.com/journal/abstracts.php?journalID=mc&articleID=122016

M3 - Article

VL - 11

SP - 30

EP - 40

JO - Medicinal Chemistry

JF - Medicinal Chemistry

SN - 1573-4064

ER -