The long-acting cholinesterase inhibitor heptyl-physostigmine attenuates the scopolamine-induced learning impairment of rats in a 14-unit T-maze.
Heptyl-physostigmine (heptyl-Phy), a new carbamate derivative of physostigmine (Phy), has been assessed for potential clinical value by evaluating its in vitro activity against human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE), its duration of in vivo activity against rat plasma AChE, and its effects on attenuating a scopolamine-induced impairment in learning performance of young rats in a 14-unit T-maze. Heptyl-Phy demonstrated potent cholinesterase inhibition, with activity similar to that of Phy against AChE, IC50 values 21.7 +/- 2.0 nM and 27.9 +/- 2.4 nM, respectively, and significantly greater than that of Phy against BChE, IC50 values 5.0 +/- 0.1 nM and 16.0 +/- 2.9 nM, respectively. Heptyl-Phy achieved maximum AChE inhibition of 92.5% at 60 min and maintained a high and relatively constant inhibition for more than 8 h. For analysis of effects on learning performance, heptyl-Phy at 1.0, 1.5, 2.0 or 3.0 mg/kg, or vehicle was administered i.p. to 52 3-month-old male Fischer-344 rats 60 min prior to maze training. Thirty minutes prior to training, each animal received either 0.9% NaCl or scopolamine hydrochloride (0.75 mg/kg). Only a 2.0 mg/kg dose of heptyl-Phy significantly reduced the number of errors in scopolamine-treated rats. The other doses did not improve any aspect of maze performance. Although the therapeutic window of heptyl-Phy did not appear wide enough for clinical use, the longer duration of action of heptyl-Phy would appear beneficial.
Iijima
S
S
Molecular Physiology and Genetics Section, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
Greig
N H
NH
Garofalo
P
P
Spangler
E L
EL
Heller
B
B
Brossi
A
A
Ingram
D K
DK
D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004597:Electroshock; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D007858:Learning / Q000187:drug effects*; D008297:Male; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012601:Scopolamine / Q000037:antagonists & inhibitors*
D002800:Cholinesterase Inhibitors; C052450:physostigmine heptyl; D010830:Physostigmine; D012601:Scopolamine; D000110:Acetylcholinesterase