title: Pharmacological properties of AC-3933, a novel benzodiazepine receptor partial inverse agonist.
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 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 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 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 levels in the hippocampus of freely moving rats (area under the curve (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.
authors: T
authors: T
authors: Hashimoto
authors: T
authors: T
authors: Kiyoshi
authors: H
authors: H
authors: Kohayakawa
authors: Y
authors: Y
authors: Iwamura
authors: N
authors: N
authors: Yoshida
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C483032:5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D009287:Naphthyridines; D010069:Oxadiazoles; D011963:Receptors, GABA-A; D013460:Sulfur Isotopes; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; D000109:Acetylcholine