Radequinil

AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor.

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.