FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, improves visual recognition memory in rhesus monkeys: comparison with physostigmine.
Our previous studies demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel antidementia piperazine derivative, exerts beneficial effects on memory deficits in various rodent models of amnesia, through activation of the somatostatin neuronal system. To extend the antiamnesic action of FK960 to nonhuman primates, FK960 was evaluated for its ability to reverse the deficits in visual recognition memory produced by muscarinic cholinergic receptor blockade by scopolamine or N-methyl-D-aspartate receptor blockade by dizocilpine (MK-801) in four rhesus monkeys performing a computer-automated version of delayed nonmatching to sample, with a list length of 20 trial-unique graphic symbols. Furthermore, the effects of FK960 were compared with those of physostigmine, a cholinesterase inhibitor. Doses of FK960 (1, 3.2, 10, 32,100, 320 or 1000 microg/kg) injected i.m. 30 min before testing minimally affected visual recognition memory when administered alone. FK960 (1, 3.2, 10 or 32 microg/kg) significantly antagonized the deficits in visual recognition memory produced by scopolamine (10 microg/kg); the same doses of the drug minimally affected the deficits produced by dizocilpine (32 microg/kg). Similarly, physostigmine (3.2, 10 or 32 microg/kg) significantly and dose-dependently restored the visual recognition memory deficits produced by scopolamine (10 microg/kg) but not those produced by dizocilpine (32 microg/kg). From these results, we conclude that FK960 improves deficits in recognition memory associated with central cholinergic hypofunction in nonhuman primates, and we suggest that the therapeutic potential of this drug for patients with dementia should be evaluated.
Matsuoka
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Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan.
Aigner
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TG
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003704:Dementia / Q000188:drug therapy*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010830:Physostigmine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012601:Scopolamine / Q000494:pharmacology; D014796:Visual Perception / Q000187:drug effects*
D001549:Benzamides; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; C102991:N-(4-acetyl-1-piperazinyl) -4-fluorobenzamide monohydrate; D018697:Nootropic Agents; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D010830:Physostigmine; D012601:Scopolamine