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

ISSN: 1875-6638 (Online)
ISSN: 1573-4064 (Print)


Volume 10, 8 Issues, 2014


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Medicinal Chemistry

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

Author(s): Viviana De Caro, Anna Lisa Scaturro, Flavia Maria Sutera, Giuseppe Avellone, Gabriella Schiera, Evelina Ferrantelli, Maria Carafa, Valerio Rizzo, Fabio Carletti, Pierangelo Sardo and Libero Italo Giannola

Affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32-90123, Palermo, Italy

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, it 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, a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, has been synthesized in good yield and characterized by FT-IR, MS, 13C and 1H- NMR analyses. The Log DpH7.4 (0.19) indicate that this new molecule potentially is able to cross biological membranes. The resistence to chemical and enzymatic hydrolysis of N-valproyl-L-Phenylalanine were also assessed. All trials suggested that the compound at the pH conditions of the entire gastro-intestinal tract remained unmodified. Moreover, the novel compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h. Toxicity assay on primary cultures of astrocytes indicated that synthetized conjugate is 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 underlines that N-valproyl-L-Phenylalanine could represent a good candidate to further investigation as new potential antiepileptic agent


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Article Details

Volume: 10
First Page: 1
Last Page: 1
Page Count: 1
DOI: 10.2174/1573406410666140507094954
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