PHENSERINE - A PHYSOSTIGMINE DERIVATIVE THAT IS A LONG-ACTING INHIBITOR OF CHOLINESTERASE AND DEMONSTRATES A WIDE DOSE RANGE FOR ATTENUATING A SCOPOLAMINE-INDUCED LEARNING IMPAIRMENT OF RATS IN A 14-UNIT T-MAZE

Phenserine ((-)-N-phenylcarbamoyl eseroline), a carbamate analog of ph ysostigmine (Phy), is a long-acting inhibitor of cholinesterase. We ha ve assessed the potential clinical value of phenserine for cholinomime tic therapy of cognitive impairments associated with aging and Alzheim er's disease by evaluating its duration of in vivo activity against ra t plasma acetylcholinesterase (AChE) and its effect on attenuating a s copolamine-induced impairment in learning performance of young rats in a shock-motivated 14-unit T-maze. Phenserine achieved maximum AChE in hibition of 73.5% at 5 min and maintained a high and relatively consta nt inhibition for more than 8 h. For analysis of effects on learning p erformance, 69, 3-month-old male Fischer-344 rats were pretrained in a straight runway to avoid electric footshock. On the following day, ea ch animal received 15 trials in the 14-unit T-maze. Sixty minutes prio r to the maze training, each rat received the first IP injection of ei ther vehicle (Tween 80, ethanol and 0.9% NaCl) or phenserine at 1.5, 3 .0, 4.0, 5.0, 7.5, or 10.0 mg/kg. Then 30 min prior to the training, e ach animal received a second IP injection of either 0.9% NaCl or scopo lamine hydrochloride (0.75 mg/kg; SCOP). Compared to the vehicle-SCOP group, all but the 7.5 mg/kg dose of phenserine significantly ameliora ted error performance, runtime, shock frequency and shock duration in SCOP-treated rats at the final block of three trials. Appearing to hav e a long effect and a wide therapeutic window, phenserine deserves fur ther study as a cognitive enhancer.