Radequinil

We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer׳s disease.

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.