Ligand-gated ion channels possess intrinsic binding sites for noncompetitive inhibitors that differ substantially in ligand specificity and structural characteristics from most binding sites found on globular proteins. We have used the nicotinic acetylcholine receptor to examine the characteristics of such diverse sites because the high-affinity binding site in the proximity of the ion channel has unusual binding interactions and ligand specificity, whereas the site of agonist activation exhibits classical structure-activity characteristics. Noncompetitive inhibitors that bind to the former site show a wide degree of structural variation and appear to associate at separate loci and in distinct orientations in the vicinity of the channel. The receptor structure appears to provide a large domain with multiple hydrophobic crevices that can bind noncompetitive inhibitors, yet binding of these inhibitors is mutually exclusive. The mutually exclusive behavior suggests that association of a single ligand is sufficient to prevent access of additional ligands to distinct sites. This could occur either by physical occlusion to the site of binding or by formation of a conformational state that will not allow entry of additional noncompetitive inhibitors.