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.
Arnal
F
F
Department of Neurology, College of Physicians & Surgeons, Columbia University, New York, N.Y. 10032.
Coté
L J
LJ
Ginsburg
S
S
Lawrence
G D
GD
Naini
A
A
Sano
M
M
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D008297:Male; D051379:Mice; D009388:Neostigmine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011729:Pyridostigmine Bromide / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D013619:Tacrine / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; C065878:norneostigmine; D009388:Neostigmine; D013619:Tacrine; C065879:norpyridostigmine; D000110:Acetylcholinesterase; D011729:Pyridostigmine Bromide; D004298:Dopamine; D009638:Norepinephrine