PHARMACOLOGICAL PROPERTIES OF AC-3933, A NOVEL BENZODIAZEPINE RECEPTOR PARTIAL INVERSE AGONIST

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 [H-3]-flumazenil binding to rat whole brain membrane with a K-i value of 5.15 +/- 0.39 nM and a 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 mu M), gradually but significantly increased [S-35] tert-butylbicyclophosphorothionate 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 a concentration range of 100-3000 nM (from 115.2% to 117.1%). AC-3933 (0.1-10 mu M) significantly enhanced KCI-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 levels in the hippocampus of freely moving rats (area under the curve (AUC(0-2 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. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.