Studies on new, centrally active and reversible acetylcholinesterase inhibitors.

We have synthesized the tertiary amines of pyridostigmine and neostigmine, 3-pyridinol dimethylcarbamate (norpyridostigmine) and 3-dimethylaminophenol dimethylcarbamate (norneostigmine) respectively, and we have tested their abilities to cross the blood-brain barrier and inhibit mouse brain AChE activity. The in vivo inhibition of AChE activity by norpyridostigmine reaches 72% at 10 minutes which is comparable to that seen with physostigmine (73% at 10 minutes). Inhibition by norneostigmine is less effective (50% at 10 minutes) and approaches that obtained with tetrahydroaminoacridine (57% at 10 minutes). These data show that both norpyridostigmine and norneostigmine cross the blood-brain barrier and that they are effective inhibitors of mouse brain AChE activity. These drugs could be useful in the treatment of memory impairment associated with Alzheimer's disease, and other memory disorders.

Synthesis and preliminary pharmacology of an internal standard for assay of neostigmine.

The synthesis of the diethyl analog of neostigmine, its preliminary pharmacology, and its use as an internal standard for the GLC assay of neostigmine are described. Both the diethyl analog and neostigmine undergo thermal demethylation in the injection port. The column selected produced satisfactory resolution and short retention times for neostigmine and the diethyl analog. The diethyl analog apparently possesses acetylcholinesterase-inhibiting properties, as evidenced by potentiation of the contractile response to acetylcholine in the ileum. In addition, acetylcholine levels in the brain were elevated slightly. Water solutions of the diethyl analog appeared to lose biological activity with time. the diethyl analog appears to be suitable for use as an internal standard for the GLC assay of neostigmine.

[Effect of x-irradiation, nicotinic acid and neostigmine methylsulfate on the interrelation between methylation and biosynthesis of tRNA]. / Vpliv rentgenivs'kogo oprominennia nikotinovo kisloti i prozerinu na vz'aemozv'iazok mizh metiliuvanniam ta biosintezom TRNK.

Experiments on rats established that tRNA of the liver under the effect of total X-irradiation (800 R), nicotinic acid and neostigmine methylsulphate proves to be hypermethylated. In this case tRNA molecules undergo conformation changes. Nicotinic acid and neostigmine methylsulphate administered to the animals under experiment an hour before irradiation favour the normalization of these indexes. As a rule, a correlation is observed between changes in methylation of tRNA and activity of their methylases. Irradiation inhibits the processes of tRNA synthesis which are normalized under the effect of nicotinic acid administered before the irradiation. Nicotinic acid and neostigmine methylsulphate produce no effect on synthesis of tRNA in the liver of normal animals. The activity of acid tRNase under the effect of nicotinic acid is not changed, under other conditions of the experiment it decreases. Irradiation against a background of nicotinic acid and neostigmine methylsulphate administered to animals and neostigmine methylsulphate administration to the intact animals inhibit the activity of alkaline tRNase.