Comparison of the effects of natural and synthetic huperzine-A on rat brain cholinergic function in vitro and in vivo.

(-)-Huperzine-A has been shown to be a promising agent for the treatment of dementia of the Alzheimer type. This substance is rare in nature. We have been able to prepare a racemic mixture of (+/-)-huperzine-A in quantity. In the absence of a chiral synthetic procedure for (-)-huperzine-A, this study sought to determine whether the racemic mixture would yield an in vitro and in vivo pharmacological profile of activity similar to that of the natural compound. The synthetic racemic mixture (+/-)-huperzine-A was 3 times less potent than (-)-huperzine-A in vitro (IC50s of 3 x 10(-7) M and 10(-7) M, respectively) because the former consisted of a racemic mixture of the compound in which the (+)-huperzine component was considerably less potent (IC50 = 7 x 10(-6) M). A comparable magnitude of effect was also observed in studies conducted in vivo, in which, over a range of 0.1-2.0 mg/kg administered intraperitoneally (i.p.), both (-)-huperzine-A and (+/-)-huperzine-A exerted significant inhibition of acetylcholinesterase activity, in all brain regions tested (hippocampus, striatum, hypothalamus and frontal cortex). This inhibition of acetylcholinesterase activity was inversely related to levels of acetylcholine measured in the hippocampus and followed the same time course of effect. (-)-Huperzine-A and (+/-)-huperzine-A were shown to be more potent than physostigmine as inhibitors of acetylcholinesterase in vitro (IC50 = 6 x 10(-7) M).