Pharmacological properties of AC-3933, a novel benzodiazepine receptor partial inverse agonist
Article Nov 05, 2013
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.
New Crystal Structure of (Ph)PINK1 Aids Understanding of Early Onset Parkinson’sArticle
Scientists have determined the crystal structure of PhPINK1 bound to it's substrate ubiquitin. Mutations of PINK1 are associated with early onset Parkinson's disease and it is expected that this information will help the design of Parkinson's therapeutics.READ MORE