amiridine and velnacrine

The effects of the compound SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) in a number of pharmacological and biochemical tests were studied and compared to those of tacrine (THA), amiridin, HP-029 and physostigmine. SM-10888 inhibited cholinesterase activity (IC50: 2.3 x 10(-7) M) in rat cortical P2 fraction with almost the same potency as THA, while SM-10888 was 2-4 times more potent than amiridin and HP-029, but about 10 times less potent than physostigmine. When given to mice p.o., SM-10888 induced central (hypothermia) and peripheral (salivation) cholinergic effects. When the ratio of the ED50 value for hypothermia to that for salivation was regarded as the index of the selectivity to the central nervous system (CNS), SM-10888 was shown to be about 3 times more selective to the CNS than the other four drugs in mice. The minimum effective dose of SM-10888 for its increasing effect on acetylcholine (ACh) content in the mouse cerebral cortex was about 10 times higher than that of physostigmine, but 5-10 times lower than those of THA, amiridin and HP-029. These results suggest that SM-10888 is an adequate drug for increasing the brain ACh content with less peripheral cholinergic side effects than THA, amiridin, HP-029 and physostigmine.

Topics: Aminacrine; Aminoacridines; Aminoquinolines; Animals; Body Temperature; Cerebral Cortex; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Male; Mice; Nucleic Acids; Physostigmine; Rats; Salivation; Tacrine

The effects of the tacrine (THA) derivative SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) on habituation and passive avoidance responses were studied in mice. We examined its effects on habituation of exploratory activity, measured by photo-cell beam interruptions in a small, simple cage and cycloheximide (CXM)- or electroconvulsive shock (ECS)-induced stepdown type passive avoidance response (PAR) failures in comparison with those of THA, amiridin, HP-029 and physostigmine. SM-10888 (6 mg/kg, p.o.) administered post-acquisition session enhanced the retention of habituation. CXM- and ECS-induced PAR failures were improved by SM-10888 (6 mg/kg, p.o.) administered at pre-training or post-training, respectively. THA enhanced the retention of habituation and improved CXM-induced PAR failure at 30 mg/kg, p.o., but did not affect ECS-induced PAR failure at 1-15 mg/kg, p.o. Amiridin and HP-029 were also effective on habituation and CXM-induced PAR failure at 40-50 mg/kg, p.o., but did not affect ECS-induced PAR failure at the tested doses. Physostigmine showed a moderate improvement only in CXM-induced PAR failure. The results indicate that SM-10888 enhanced habituation and improved PAR failures at much lower doses than THA. This seems to depend on its high selectivity to the central nervous system.

Topics: Aminacrine; Aminoacridines; Aminoquinolines; Animals; Avoidance Learning; Cholinesterase Inhibitors; Cycloheximide; Electroshock; Exploratory Behavior; Habituation, Psychophysiologic; Male; Mice; Physostigmine; Tacrine