Receptor interaction profile and CNS general pharmacology of metrifonate and its transformation product dichlorvos in rodents

• Published in: Drug development research Vol. 38; no. 1; pp. 31 - 42
• Main Authors: Hinz, Volker C., Blokland, Arjan, van der Staay, Franz-Josef, Gebert, Irmingard, Schuurman, Teunis, Schmidt, Bernard H.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.05.1996; Wiley-Liss
• Subjects: Biological and medical sciences; cholinergic symptoms; Cholinergic system; dichlorvos; general CNS pharmacology; Medical sciences; metrifonate; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Enzyme; Metabolite; Interaction; Rodentia; Central nervous system; Oral administration; Enzyme inhibitor; Esterases; Biological activity; Cholinesterase; Carboxylic ester hydrolases; Cholinergic pathway; Vertebrata; Mammalia; Animal; Metrifonate; Dichlorvos; Hydrolases; Brain (vertebrata); Biological receptor
• DOI: 10.1002/(SICI)1098-2299(199605)38:1<31::AID-DDR4>3.0.CO;2-M
• ISSN: 0272-4391

In this study we assessed the possible effects of the putative Alzheimer therapeutic, metrifonate (39, 120, 390 μmol/kg), and its active transformation product, dichlorvos (4.5, 13.6, 45 μmol/kg), on the mammalian central nervous system (CNS). We did this by (1) investigating the receptor interaction profile of the two compounds in a range of in‐vitro radioligand binding assays, and (2) by studying the acute compound effects in rats and mice using a battery of behavioral tests after a single oral administration. Metrifonate and dichlorvos failed to displace various radioligands from their respective receptor binding sites on cell membranes at a concentration of 10 μM. In particular, there was no high‐affinity interaction with muscarinic or nicotinic acetylcholine receptor binding in‐vitro. In the modified Irwin test (rat) both compounds induced transient cholinergic symptoms after oral administration of a single dose of 390 μmol/kg metrifonate and 13.6–45 μmol/kg dichlorvos. The observed symptoms, such as salivation, tremor, and diarrhea, lasted for up to 75 min. In the open field test (rat) metrifonate increased the number of rearings at all doses, whereas dichlorvos had no effect on the parameters tested. Both compounds dose‐dependently reduced the pentylenetetrazole threshold dose in mice. In this test, only the highest dose of metrifonate, but all doses of dichlorvos, 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 anesthesia in mice. Metrifonate induced hypothermia in rats only at the dose of 390 μmol/kg. Dichlorvos did not affect body temperature. No analgesic potential was observed in the hot‐plate test in mice. Furthermore, metrifonate and dichlorvos neither influenced motor coordination nor exhibited any cataleptic potential when administered to rats. Taken together, at cognition‐enhancing doses, metrifonate (39–120 μmol/kg) is safe and well tolerated. The adverse symptoms observed at higher doses, together with the apparent lack of high‐affinity interaction with neurotransmitter receptors in brain tissue and the similar profile of the active transformation product, dichlorvos, support the assumption that these compounds mediate a highly selective activation of the cholinergic system. © 1996 Wiley‐Liss, Inc.