Oxadiazolidinones: irreversible inhibition of cholinesterases and effects on acetylcholine receptors.

Inhibition of four acetylcholinesterases (AChE) and a butyrylcholinesterase (BuChE) by 3-(2,3-dihydro-2,2-dimethyl-benzofuran-'7-yl)-5-methoxy-1,3,4-oxadiaz ol-2(3H)-one (DBOX) and 3-(2-methoxyphenyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (MPOX) was measured by the Ellman spectrophotometric method. Both oxadiazolidinones inhibited AChE and BuChE irreversibly and with quasi first order kinetics. DBOX was 2-3 orders of magnitude more potent than MPOX. Housefly brain AChE and horse serum BuChE were more sensitive than AChEs of red blood cells or eel and Torpedo electric organs. Aldicarb, a carbamate anticholinesterase, which protected Torpedo AChE against irreversible phosphorylation by DFP, also protected it against irreversible inhibition by DBOX and MPOX. It is suggested that the nonesteratic oxadiazolidinones are converted to carbanillates on the surface of the enzyme, then acylate the active site of ChEs, producing carbanillated enzymes. At higher concentrations, the two oxadiazolidinones also affected the specific binding of (125I) alpha-bungarotoxin (alpha-BGT) and [3H]perhydrohistrionicotoxin (H12-HTX) to Torpedo nicotinic ACh-receptors, but did not affect the specific binding of [3H]quinuclidinyl benzilate (QNB) to rat brain muscarinic ACh-receptors.