RECEPTOR INTERACTION PROFILE AND CNS GENERAL PHARMACOLOGY OF METRIFONATE AND ITS TRANSFORMATION PRODUCT DICHLORVOS IN RODENTS

In this study we assessed the possible effects of the putative Alzheim er therapeutic, metrifonate (39, 120, 390 mu mol/kg), and its active t ransformation product, dichlorvos (4.5, 13.6, 45 mu mol/kg), on the ma mmalian central nervous system (CNS). We did this by (1) investigating the receptor interaction profile of the two compounds in a range of i n-vitro radioligand binding assays, and (2) by studying the acute comp ound effects in rats and mice using a battery of behavioral tests afte r a single oral administration. Metrifonate and dichlorvos failed to d isplace various radioligands from their respective receptor binding si tes on cell membranes at a concentration of 10 mu M. In particular, th ere was no high-affinity interaction with muscarinic or nicotinic acet ylcholine receptor binding in-vitro. In the modified Irwin test (rat) both compounds induced transient cholinergic symptoms after oral admin istration of a single dose of 390 mu mol/kg metrifonate and 13.6-45 mu mol/kg dichlorvos. The observed symptoms, such as salivation, tremor, and diarrhea, lasted for up to 75 min. In the open field test (rat) m etrifonate increased the number of rearings at all doses, whereas dich lorvos had no effect on the parameters tested. Both compounds dose-dep endently reduced the pentylenetetrazole threshold dose in mice. In thi s test, only the highest dose of metrifonate, but all doses of dichlor vos, caused a significant reduction of the convulsion threshold dose. Metrifonate and dichlorvos did not influence traction ability in mice. Metrifonate and dichlorvos did not influence hexobarbital-induced ane sthesia in mice. Metrifonate induced hypothermia in rats only at the d ose of 390 mu mol/kg. Dichlorvos did not affect body temperature. No a nalgesic potential was observed in the hot-plate test in mice. Further more, metrifonate and dichlorvos neither influenced motor coordination nor exhibited any cataleptic potential when administered to rats. Tak en together, at cognition-enhancing doses, metrifonate (39-120 mu mol/ kg) is safe and well tolerated. The adverse symptoms observed at highe r doses, together with the apparent lack of high-affinity interaction with neurotransmitter receptors in brain tissue and the similar profil e of the active transformation product, dichlorvos, support the assump tion that these compounds mediate a highly selective activation of the cholinergic system. (C) 1996 Wiley-Liss, Inc.