title: Anticonvulsant activity of new GABA prodrugs.
abstract: 4-(3,4-Dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)-butyric acid (7) and its ethyl (6), two potential y-aminobutyric acid (GABA) prodrugs, were synthesized and studied to determine their stability in aqueous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous media, (t((1/2)) = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-dioxo-2 H-I,3-benzoxazine ring underwent enzymatic hydrolysis (t((1/2)) =5.8 h) in compound 7, whereas in compound 6 it seemed not to be opened by mouse plasma esterases within the observation lime (3 h). Both compounds were tested for their central nervous system activity by using both anticonvulsive and behavioral tests. The anticonvulsive study was performed using the convulsive agent pentetrazole (PTX) and bicuculline. The anticonvulsive study indicated that compound both compounds 6 and 7 (10, 20 and 40 mg/kg, i.p.), injected 60 min before PTX (75 mg/kg, i.p.) or bicuculline (10 microg/intracerebroventricular (i.c.v.)/mouse) induced a dose-dependent and significant reduction of the convulsive activity of PTZ and bicuculline whereas it was ineffective if injected immediately before the convulsive agent. Both compounds 6 and 7 (10, 20 and 40 mg/kg, i.p.) did not significantly modify animal behavior or the nociceptive threshold of the animals. However, in PTZ- and bicuculline- treated mice, compound 7 showed significant activity, compared to compound 6, because it was active at relatively low doses. The behavior elements considered were locomotor activity, motor coordination, catalepsy, behavior and antinociception. The results of the behavoral study indicate that these new GABA mimetic drugs did not modify the animal behavior. Our data indicate that these new GABA mimetic drug possesses good anticonvulsive activity without altering the animalbehavior and their ability to block bicuculline-induced convulsions suggests that they could be a GABA(A) mimetic drug. Furthermore, since these compounds are able to act after systemic administration, our data suggest that these new GABA mimetic drug cross the blood-brain barrier.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, (84084) Fisciano, Salerno, Italia. annacap@unisa.it
authors.forename: A
authors.initials: A
authors.lastname: Capasso
authors.forename: C
authors.initials: C
authors.lastname: Gallo
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004950:Esterases / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D012995:Solubility; D014867:Water / Q000737:chemistry; D005680:gamma-Aminobutyric Acid
chemical_list: D000927:Anticonvulsants; D058787:GABA-A Receptor Antagonists; D011355:Prodrugs; D011963:Receptors, GABA-A; D014867:Water; D005680:gamma-Aminobutyric Acid; D004950:Esterases