Pharmacological evaluation of phenyl-carbamates as CNS-selective acetylcholinesterase inhibitors.
The pharmacological and clinical properties of a novel phenyl carbamate acetylcholinesterase (AChE) inhibitor, SDZ ENA 713 are described. In animals and human subjects this compound showed superior chemical stability, oral bioavailability and a longer duration of action than physostigmine. SDZ ENA 713 produced a 10-fold greater inhibition of AChE in the hippocampus and cortex than in the heart and skeletal muscle, which explains its relatively low toxicity and freedom from cholinergic side effects. The selective effect in the cortex and hippocampus may be due to its preferential inhibition of the G1 form of the enzyme, which is present in relatively higher concentrations in these brain areas. Evidence of a selective hippocampal action was obtained in normal human subjects in whom REM sleep density was increased at doses that had no effect on plasma cholinesterase. If memory impairments in AD are related to a lack of cholinergic activity in cortical and hippocampal brain areas, SDZ ENA 713 should produce significant symptomatic improvement.
Weinstock
M
M
Department of Pharmacology, School of Pharmacy, Hebrew University Hadassah Medical Centre, Jerusalem, Israel.
Razin
M
M
Chorev
M
M
Enz
A
A
D000818:Animals; D001921:Brain / Q000201:enzymology*; D002219:Carbamates / Q000494:pharmacology* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D048448:Phenylcarbamates; D000068836:Rivastigmine
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000068836:Rivastigmine