KA-672 inhibits rat brain acetylcholinesterase in vitro but not in vivo

KA-672, a lipophilic benzopyranone derivative which is currently under deve lopment as a cognitive enhancer and antidementia drug, has previously been shown to have facilitatory effects on teaming and memory in rats at doses o f 0.1-1 mg/kg. We now report that KA-672 inhibited the activity of acetylch olinesterase (AChE), measured in vitro in rat brain cortical homogenate, wi th an IC50 value of 0.36 mu M indicating that KA-672 may improve cognitive functions as a consequence of AChE inhibition. However, when we employed th e microdialysis procedure to monitor acetylcholine (ACh) release from rat h ippocampus, no effect of KA-672 (0.1-10 mg/kg) was found, indicating a lack of inhibition of brain AChE under in vivo-conditions. [C-14]-labelled KA-6 72 was found to easily penetrate the blood-brain barrier, and an apparent c oncentration of 0.22 nmol/g brain (equivalent to 0.39 mu M tissue concentra tion) was calculated following an i.p. injection of 1 mg/kg KA-672. However , no labelled substance could be detected in hippocampal microdialysates or in cerebrospinal fluid (CSF) taken from the cisterna magna, indicating tha t the concentration of KA-672 in brain extracellular fluid must have been b elow 0.01 mu M. We conclude that KA-672 is a potent AChE inhibitor, an acti vity which, however, does not contribute to its behavioural effects in vivo because the lipophilic drug does not reach sufficient concentrations in th e extracellular fluid, apparently due to cellular sequestration. (C) 1999 E lsevier Science Ireland Ltd. All rights reserved.