1. The effects of tacrine (9-amino-1,2,3,4-tetrahydroacridine), velnacrine (HP029, 9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate), suronacrine (HP128, 9-benzylamino-1,2,3,4-tetrahydroacridin-1-ol maleate), and 3,4-diaminopyridine on neuromuscular transmission were compared on isolated nerve-muscle preparations. 2. Tacrine, HP029, and 3,4-diaminopyridine augmented responses of chick biventer cervicis preparations to nerve stimulation, with tacrine and HP029 increasing responses to exogenously applied acetylcholine. HP128 blocked responses to nerve stimulation and to carbachol, but increased responses to acetylcholine. 3. In mouse diaphragm preparations that were partially paralysed by tubocurarine or low calcium solutions, tacrine, HP029, and 3,4-diaminopyridine reversed the twitch block. HP128 deepened the block. 4. In mouse triangularis sterni preparations, tacrine and HP029 prolonged the decay phase of endplate potentials and miniature endplate potentials, but had no effect on quantal content at 36 degrees C; above 10 microM, they reduced endplate potential amplitude. 3,4-Diaminopyridine increased quantal content without affecting the time course of the endplate potentials. HP128 (1-10 microM) had no effect on amplitude or time course of endplate potentials, but reduced their amplitude at higher concentrations. 5. Extracellular recording of nerve terminal currents from triangularis sterni preparations revealed that 3,4-diaminopyridine and HP128 had a selective blocking action on the waveform associated with K+ currents, tacrine reduced and prolonged the K(+)-related waveform, and HP029 had nonselective blocking actions only seen at high concentrations. 6. Tacrine and HP029 behave predominantly as anticholinesterase agents, while HP128 has weaker anticholinesterase actions that are masked by cholinoceptor blockade. Tacrine and HP128, but not HP029, have some blocking actions on K+ currents of mouse motor nerve terminals.
Title: Pharmacological and biochemical assessment of SM-10888, a novel cholinesterase inhibitor Natori K, Okazaki Y, Irie T, Katsube J Ref: Japanese Journal of Pharmacology, 53:145, 1990 : PubMed
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.
