6533b7cffe1ef96bd1257cd6

RESEARCH PRODUCT

N-valproyl-L-tryptophan for CNS-targeting: synthesis, characterization and efficacy in vitro studies of a new potential antiepileptic drug.

Pierangelo SardoViviana De CaroGiuseppe FerraroLiliana LamartinaValerio RizzoMaria Gabriella SiragusaFabio CarlettiSimonetta FrisciaGiulia GiandaliaLibero Italo Giannola

subject

Malemedicine.medical_treatmentHippocampal formationPharmacologyIn Vitro TechniquesBlood–brain barrierSettore BIO/09 - FisiologiaHippocampuschemistry.chemical_compoundDrug StabilityIn vivoDrug DiscoverymedicineAnimalsRats WistarValproic AcidEpilepsyDipeptidesAminoacidic derivative Antiepileptic Drug CNS-Targeting Enzymatic Stability Seizure Like Events Model Valproic acidIn vitroElectrophysiological PhenomenaRatsmedicine.anatomical_structureAnticonvulsantchemistrySettore CHIM/09 - Farmaceutico Tecnologico ApplicativoAnticonvulsantsPharmacophoreDerivative (chemistry)medicine.drug

description

A new aminoacidic derivative of valproic acid (VPA) has been synthesized and characterized by analytical and spectral data. The rationale for the preparation of such potential antiepileptic agent is based on the observation that chemical combination of the anticonvulsant pharmacophore, VPA with essential aminoacids could afford more effective and less toxic actives. The synthesis, characterization, physico-chemical parameters functional for crossing Blood Brain Barrier of N-valproyl-L-tryptophan (4) are reported. The Log D pH7.4 (0.3) indicates that (4) is adequate to cross biological membranes. Its chemical and enzymatic stability were assessed. The experiments indicate high stability of compound (4) at pH conditions of physiological fluids. Moreover, both in plasma and in cerebral enzymatic environments compound (4) doesnt undergo cleavage after 24 h. The anticonvulsant activity of the new compound was assessed against epileptic burst discharges evoked in vitro in rat hippocampal slices (Seizure like events - SLEs) and compared with that of the widely used VPA. Compound (4), even at the lower tested concentration, when compared to VPA, showed an improved protective effect against hippocampal seizures. The collected data suggest that compound (4) could be considered a very valuable candidate for subsequent in vivo evaluation as new potential antiepileptic drug.

yearjournalcountryeditionlanguage
2010-04-02Medicinal chemistry (Shariqah (United Arab Emirates))
10.2174/157340611794072733https://pubmed.ncbi.nlm.nih.gov/21235514