How do sulfonylureas approach their receptor in the B-cell plasma membrane?

Since it was unknown whether the uncharged or the anionic form of hypoglycemic sulfonylureas and meglitinide is the effective modulator of ATP-dependent K+ channels and insulin secretion, we studied the inhibitory effects of tolbutamide and meglitinide on the ATP-dependent K+ current at different external pH. The whole-cell configuration of the patch-clamp technique was used in mouse pancreatic B-cells. When the concentrations of the undissociated forms of these drugs were kept constant at increasing pH of the bath solution (6.4 to 8.4), the rate of development and the degree of K+ channel block varied only slightly. Raising the pH-value in the bath solution at constant total concentration of tolbutamide diminished both the rate of development and the degree of K+ channel block. It is concluded that the undissociated forms of tolbutamide and related compounds are the effective forms. Examination of the K+ current records during the application and removal of different concentrations of tolbutamide, meglitinide, glipizide and glibenclamide at pH 7.4 indicated that the kinetics of the current records reflected not only association and dissociation of the drug-receptor complex but perhaps also the kinetic of drug distribution between bath and the lipid phase of the plasma membrane. As there is evidence against an interaction between sulfonylureas and their receptor via a binding site freely accessible from the cytoplasm, the drugs probably get access to their binding site on the receptor from the lipid phase of the B-cell plasma membrane.