AbstractThe interaction of diisopropylfluorophosphate (DFP) with the nicotinic acetylcholine (ACh) receptor of Torpedo electric organ was studied, using [3H]‐phencyclidine ([3H]‐PCP) as a reporter probe. Phencyclidine binds with different kinetics to resting, activated, and desensitized receptor conformations. Although DFP did not inhibit binding of [3H]‐ACh or 125I‐α‐bungarotoxin (BGT) to the receptor recognition sites and potentiated in a time‐dependent manner [3H]‐PCP binding to the receptor's high‐affinity allosteric site, it inhibited the ACh or carbamylcholine‐stimulated [3H]‐PCP binding. This suggested that DFP bound to a third kind of site on the receptor and affected receptor conformation. Preincubation of the membranes with DFP increased the receptor's affinity for carbamylcholine by eightfold and raised the pseudo‐first‐order rate of [3H]‐PCP binding to that of an agonist‐desensitized receptor. Accordingly, it is suggested that DFP induces receptor desensitization by binding to a site that is distinct from the recognition or high‐affinity noncompetitive sites.