A-4166 is a new type of oral hypoglycemic agent that does not contain a sulfonylurea moiety. To clarify the mechanism of insulin secretion by A-4166, a specific receptor for A-4166 was investigated in a hamster pancreatic β cell line (HIT T-15 ), using [3H]A-4166 or [3H]glibenclamide as a ligand. The saturation binding of [3H]A-4166 to HIT cell membranes was not observed up to 10 μM. In the displacement study, unlabeled A-4166 inhibited [3H]A-4166 binding to HIT cell membranes, but glibenclamide did not. On the other hand, A-4166 inhibited [3H]glibenclamide binding to the sulfonylurea receptor (K(i) = 248 nM). A-4166 inhibited 86Rb efflux from HIT cells (IC50 = 350 nM). The EC50 for insulin secretion by A-4166 was 20 μM in HIT cells when they were incubated for 30 min in Krebs-Ringer bicarbonate buffer containing 16 mM HEPES supplemented with 5 mg/mL BSA in the absence of glucose. These data demonstrate the possibility of the presence of two kinds of binding sites for A-4166: one of them is the sulfonylurea receptor, and the other might be a binding site specific for A-4166.
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