title: In vivo pharmacological characterization of AC-3933, a benzodiazepine receptor partial inverse agonist for the treatment of Alzheimer's disease.
abstract: GABAergic neurons are known to inhibit neural transduction and therefore negatively affect excitatory neural circuits in the brain. We have previously reported that 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1,6-naphthyridin-2(1H)-one (AC-3933), a partial inverse agonist for the benzodiazepine receptor (BzR), reverses GABAergic inhibitory effect on cholinergic neurons, and thus enhances acetylcholine release from these neurons in rat hippocampal slices. In this study, we evaluated AC-3933 potential for the treatment of Alzheimer's disease, a disorder characterized by progressive decline mainly in cholinergic function. Oral administration of AC-3933 (0.01-0.03mg/kg) resulted in the amelioration of scopolamine-induced amnesia, as well as a shift in electroencephalogram (EEG) relative power characteristic of pro-cognitive cholinergic activators, such as donepezil. In addition, treatment with AC-3933 even at the high dose of 100mg/kg p.o. produced no seizure or anxiety, two major adverse effects of BzR inverse agonists developed in the past. These findings indicate that AC-3933 with its low risk for side effects may be useful in the treatment of Alzheimer's disease.
authors: Drug Development Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: yuki-hatayama@ds-pharma.co.jp.
authors: Y
authors: Y
authors: Hatayama
authors: Drug Development Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors: T
authors: T
authors: Hashimoto
authors: Innovative Drug Discovery Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors: H
authors: H
authors: Kohayakawa
authors: Drug Development Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors: T
authors: T
authors: Kiyoshi
authors: Drug Development Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors: K
authors: K
authors: Nakamichi
authors: Research Administration, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors: T
authors: T
authors: Kinoshita
authors: Innovative Drug Discovery Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors: N
authors: N
authors: Yoshida
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000647:Amnesia / Q000188:drug therapy; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D054314:Drug Inverse Agonism; D004569:Electroencephalography; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C483032:5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; D058787:GABA-A Receptor Antagonists; D009287:Naphthyridines; D010069:Oxadiazoles
keywords: Alzheimer’s disease; GABAA receptor; benzodiazepine receptor; cognitive function; inverse agonist