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 drug in treatment of 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, (13)C and (1)H- NMR analyses. The Log D(pH7.4) 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.

Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells

“…4,7 VPA also efficiently prevents childhood epilepsies and infantile spasms. 4,8 VPA-mediated acetylation of specific histone fractions progresses in the activation of genes associated with specific disorders; the molecular mechanisms and pathways involved are just beginning to be understood. For instance, VPA treatment increased histone acetylation results in the upregulation of genes responsible for memory formation that normally is deficient in phobias or panic.…”

Amino-Acid-Conjugated Natural Compounds: Aims, Designs and Results

“…Conjugation with amino acids is one of the means of remodelling the structure of natural compounds [ 14 ]. Amino acids are chosen based on the premise that they are the most quintessential monomers of living systems [ 15 , 16 ].…”