title: Pharmacological and biochemical assessment of SM-10888, a novel cholinesterase inhibitor.
abstract: 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.
authors.affiliation: Research Laboratories, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Natori
authors.forename: Y
authors.initials: Y
authors.lastname: Okazaki
authors.forename: T
authors.initials: T
authors.lastname: Irie
authors.forename: J
authors.initials: J
authors.lastname: Katsube
mesh_terms: D000585:Aminacrine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000609:Aminoacridines / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009696:Nucleic Acids / Q000378:metabolism; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D012472:Salivation / Q000187:drug effects; D013619:Tacrine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000609:Aminoacridines; D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D009696:Nucleic Acids; C065164:9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine; D013619:Tacrine; D000585:Aminacrine; D010830:Physostigmine; C049860:amiridine; C056424:velnacrine