title: N-valproyl-L-tryptophan for CNS-targeting: synthesis, characterization and efficacy in vitro studies of a new potential antiepileptic drug.
abstract: 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) doesn't 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.
authors.affiliation: Dipartimento di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy. vdecaro@unipa.it
authors.forename: Viviana
authors.initials: V
authors.lastname: De Caro
authors.forename: Giulia
authors.initials: G
authors.lastname: Giandalia
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Siragusa
authors.forename: Liliana
authors.initials: L
authors.lastname: Lamartina
authors.forename: Simonetta
authors.initials: S
authors.lastname: Friscia
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Sardo
authors.forename: Fabio
authors.initials: F
authors.lastname: Carletti
authors.forename: Valerio
authors.initials: V
authors.lastname: Rizzo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ferraro
authors.forename: Libero Italo
authors.initials: LI
authors.lastname: Giannola
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000138:chemical synthesis* / Q000627:therapeutic use*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000927:Anticonvulsants; D004151:Dipeptides; C558142:N-valproyl-L-tryptophan