DETERMINATION OF 1-(4-AMINOPHENYL)-4-METHYL-7,8-METHYLENE-DIOXY-2,3-BENZODIAZEPINE BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY-DIODE ARRAY DETECTION IN PLASMA AND BRAIN IN HEALTHY AND HYPOXIC-ISCHAEMIC RATS

摘要

The 2,3-benzodiazepine class of compounds is one of several drug classes extensively studied for the treatment of stroke. 1-(4'-Aminophenyl)-4-methyl-7, 8-methylene-dioxy-2,3-benzodiazepine (GYKI-52466) was the first molecule of this class of selective non-A/-methyl-D-aspartate (NMDA) receptor antagonists to be successfully differentiated pharmacologically from other benzodiazepine derivatives (Chapman et al., 1991; Donevan and Rogawski, 1993) (Fig. 1). Surprisingly, early studies of GYKI-52466 indicated that it did not act as a classical benzodiazepine, exhibiting little if any effect via GABA_A receptors (Tarnawa et al., 1989). Instead, GYKI-52466 was found to act as a selective non-competitive AMPA receptor negative allosteric modulator, with in vitro IC_50's of 13-22 muM (Donevan and Rogawski, 1993; Zorumski et al., 1993; Bleakman et al., 1996). This mode of action was subsequently assumed to underlie its anticonvulsant and neuroprotective efficacy in numerous animal models of seizure (De Sarro et al., 1998a,b, 2003) and stroke (Erdo et al., 2005; Gressens et al., 2005; Denes et al., 2006; Matucz et al., 2006; Gigler and Moricz, 2007), at doses ranging from 10 to 30 mg/kg. However, consistent with its activity as an ionotropic AMPA receptor blocker, an adverse side effect profile consisting of sedation, ataxia, and confusion was observed for GYKI-52466 doses as low as 10-15 mg/kg, thus limiting its therapeutic utility (Donevan et al., 1994; Borowicz et al., 2001).