Stimulation of insulin release by benzoic acid derivatives related to the non-sulphonylurea moiety of glibenclamide: structural requirements and cellular mechanisms.

A decrease in membrane permeability to K+ is the first critical event occurring in pancreatic B-cells upon stimulation by hypoglycemic sulphonylureas. Compound HB 699 (4-[2-(5-chloro-2-methoxybenzamido)ethyl]benzoic acid), the non-sulphonylurea moiety of glibenclamide stimulates B-cells by the same mechanisms as glibenclamide itself. Selected derivatives of HB 699 were used to test, with isolated mouse islets, whether this property is due to the benzoic acid end of the molecule (not present in glibenclamide) or to another active site (also present in glimenclamide). Of the two halves of HB 699, p-ethylbenzoic acid, but not 5-Cl-2-methoxybenzamide, was weakly effective. Replacement of the carboxyl group of HB 699 by various non-acidic groups decreased but did not abolish the ionic and secretory effects on B-cells. Modifications of the other end of the molecule altered the efficacy in both directions. Removal of the substituents on the benzamide ring decreased the efficacy, whereas replacement of the 5-Cl-2-methoxybenzyl group by a 1,1-diphenylethyl group or a 9-fluorenylmethyl group led to substantially more active compounds. Their cellular mode of action was however not modified. It is concluded that compound HB 699 contains two active sites, both of which can trigger insulin release by decreasing K+ permeability of the B-cell membrane. K channels appear to possess, not a sulphonylurea receptor, but a target site for various chemical groups. The chemical environment of the latter may also determine their efficacy by modulating their access to the channel.