A series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones were synthesized. These bicylic derivatives contain both the 2-pyrrolidinone and 4-imidazolidinone nuclei, already recognized as important for cognition enhancing activity. In addition, these structures maintain the backbone of piracetam and oxiracetam with the acetamide side chain restricted in a folded conformation. Their ability to reverse scopolamine-induced amnesia was assessed in a one trial, step-through, passive avoidance paradigm. The main features observed are a potent antiamnestic activity after ip administration (minimal effective dose being between 0.3 and 1 mg/kg ip for most compounds), the presence of a bell-shaped dose-response curve and, generally, a reduction of biological activity after po administration. However, the unsubstituted compound (15, dimiracetam) shows no evidence of a bell-shaped dose-response curve and completely retains activity when given orally, being 10-30 times more potent than the reference drug oxiracetam.
The effects exerted by oxiracetam on the disruption of performance induced by scopolamine in the radial arm maze were investigated in overtrained rats. Scopolamine induced a dose-related decrease in the efficiency of responding and an increase of running time. The effect of the SC injection of 0.2 mg/kg scopolamine on the efficiency of responding was antagonized by the IP administration of 30 mg/kg oxiracetam, while the effect on running time induced by the same dose of scopolamine was not. Physostigmine (0.3 mg/kg SC) antagonized both effects of 0.2 mg/kg scopolamine. Methylscopolamine, at the dose of 0.2 mg/kg SC, was devoid of any effect on both parameters. Increasing the dose of methylscopolamine to 0.63 mg/kg did cause serious peripheral effects which eventually prevented some animals from completing the task. Similar peripheral effects were observed after administration of 0.63 mg/kg scopolamine. The effects of this dose of scopolamine on efficiency and running time were not antagonized by pretreatment with 100 mg/kg oxiracetam. Oxiracetam alone (30 or 100 mg/kg IP) did not modify the performance of previously trained rats. The present results suggest that oxiracetam selectively restores cholinergic mechanisms which are involved in learning and memory.
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