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 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.
authors.forename: Viviana
authors.initials: V
authors.lastname: De Caro
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Scaturro
authors.forename: Flavia Maria
authors.initials: FM
authors.lastname: Sutera
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Avellone
authors.forename: Gabriella
authors.initials: G
authors.lastname: Schiera
authors.forename: Evelina
authors.initials: E
authors.lastname: Ferrantelli
authors.forename: Maria
authors.initials: M
authors.lastname: Carafa
authors.forename: Valerio
authors.initials: V
authors.lastname: Rizzo
authors.forename: Fabio
authors.initials: F
authors.lastname: Carletti
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Sardo
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32-90123, Palermo, Italy. viviana.decaro@unipa.it.
authors.forename: Libero Italo
authors.initials: LI
authors.lastname: Giannola
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D001692:Biological Transport; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D004355:Drug Stability; D005071:Evoked Potentials / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008297:Male; D008867:Microtomy; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; C000601251:N-valproylphenylalanine; D010649:Phenylalanine; D014635:Valproic Acid