European Neuropsychopharmacology 7 (1997) 57–63 Anticonvulsive activity of a new GABA mimetic drug a b, c d d e * A. Capasso , A. Biondi , F. Palagiano , F.P. Bonina , L. Montenegro , P. de Caprariis , b b E. Pistorio , L. Sorrentino a School of Pharmacy, University of Salerno, Piazza Vittorio Emanuele 9 (84084), Penta di Fisciano, Salerno, Italy b Department of Experimental Pharmacology, University of Naples Federico II, via Domenico Montesano 49 (80131), Naples, Italy c Department of Pharmaceutical Chemistry, University of Naples Federico II, via Domenico Montesano 49 (80131), Naples, Italy d Institute of Pharmaceutical Chemistry, University of Catania, Viale A. Doria 6 (95125), Catania, Italy e Institute of Pharmaceutical Analysis, University of Sassari, via Muroni 23 / A (07100), Sassari, Italy Received 14 February 1996; accepted 22 October 1996 Abstract This study examines the pharmacological profile of a new GABA mimetic drug, 4-[(2H)-1,3-benzoxazine-2,4(3H)-dione]-butyric acid (BXDBA), using both a behavioral and an anticonvulsive study. The behavior elements considered were locomotor activity, motor coordination, catalepsy, behavior and antinociception. The anticonvulsive study was performed using the convulsive agent bicuculline. BXDBA [10, 20 and 40 mg / kg, intraperitoneally (i.p.)] did not significantly modify animal behavior or the nociceptive threshold of the animals. The anticonvulsive study indicated that BXDBA (10, 20 and 40 mg / kg, i.p.), injected 60 min before bicuculline (10 mg / intracerebroventricular (i.c.v.) / mouse) induced a dose-dependent and significant reduction of the convulsive activity of bicuculline whereas it was ineffective if injected immediately before the convulsive agent. Our data indicate that this new GABA mimetic drug possesses good anticonvulsive activity and its ability to block bicuculline-induced convulsions suggests that it could be a GABA mimetic A drug. Furthermore, since BXDBA is able to act after systemic administration, our data suggest that this new GABA mimetic drug crosses the blood–brain barrier. 1997 Elsevier Science B.V. All rights reserved. Keywords: g-Aminobutyric acid (GABA); Anticonvulsant; Systemic administration 1. Introduction GABA prodrugs have been reported in the literature, such as methyl ester hydrochloride (Bianchi et al., 1983), GABA is a neurotransmitter which may be useful in the various aliphatic, lipid and steroid esters (Shashoua et al., treatment of Huntington’s disease (Enna et al., 1977), 1984; Jacob et al., 1985), some glycerol lipid derivatives epilepsy (Bakay and Harris, 1981), Parkinson’s disease (Jacob et al., 1990; Deverre et al., 1991; Lambert et al., (Nishino et al., 1988). Unfortunately, peripheral adminis- 1993), isonicotinoyl amides (Matsuyama et al., 1984), tration of GABA is not effective because, under normal pivaloyl and benzoyl amides (Galzigna et al., 1978) and conditions, it crosses the blood–brain barrier (BBB) very dihydropyridine derivative (Bodor, 1989). poorly, presumably as a result of its low lipophilicity In this paper, we describe the pharmacological evalua- (Meldrum and Hort, 1974). The brain penetration index tion, as anticonvulsant activity in mice, of a new GABA (BPI) for GABA was found to be 1%, regardless of the prodrug (BXDBA). The choice of the 1,3-benzoxazine-2,4- mode of administration and the dose (Shashoua et al., dione ring as the promoiety to obtain GABA prodrugs was 1984). Among the different strategies (Madrid et al., 1991) based on the following considerations: (1) This structure used to increase the uptake of GABA into the brain, the should notably enhance the lipophilicity of the parent drug prodrug approach is one of the most promising. Different by masking its aminic group; (2) the hydrolytic opening of the N-substituted (2H)-1,3-benzoxazine-2,4(3H)-dione * Corresponding author. ring should generate (Kahns and Bundgaard, 1991; Kahns 0924-977X / 97 / $17.00  1997 Elsevier Science B.V. All rights reserved PII S0924-977X(96)00390-2