T. Hashimoto, T. Kiyoshi, H. Kohayakawa, Y. Iwamura, N. Yoshida
Abstract: We investigated in this study the pharmacological properties of AC-3933 [5-(3-methoxyphenyl)-3-(5-methyl-1, 2, 4-oxadiazol-3-yl)-1, 6-naphthyridin-2(1H)-one], a novel benzodiazepine receptor (BzR) partial inverse agonist. AC-3933 potently inhibited [3H]-flumazenil binding to rat whole brain membrane with a Ki value of 5.15 ± 0.39 nM and a γ-aminobutyric acid (GABA) ratio of 0.84 ± 0.03. AC-3933 exhibited almost no affinity for the other receptors, transporters and ion channels used in this study. In addition, AC-3933, in the presence of GABA (1 μM), gradually but significantly increased [35S] tert-butylbicyclophosphorothionate ([35S]-TBPS) binding to rat cortical membrane to 117.1% of the control (maximum increase ratio) at 3000 nM. However, this increase reached a plateau at 30 nM with hardly any change at concentration range of 100 nM to 3000 nM (from 115.2% to 117.1%). AC-3933 (0.1-10 μM) significantly enhanced KCl-evoked acetylcholine (ACh) release from rat hippocampal slices in a concentration dependent manner. Moreover, in vivo brain microdialysis showed that intragastric administration of AC-3933 at the dose of 10 mg/kg significantly increased extracellular ACh level in the hippocampus of freely moving rats (AUC0-2 h of ACh level; 288.3% of baseline). These results indicate that AC-3933, a potent and selective BzR inverse agonist with low intrinsic activity, might be useful in the treatment of cognitive disorders associated with degeneration of the cholinergic system.