Studies on the N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) receptor in HIT T-15 cells - Displacement of [H-3]glibenclamide

被引:20
作者
Fujita, T
Seto, Y
Kondo, N
Kato, R
机构
[1] KEIO UNIV, SCH MED, DEPT PHARMACOL, TOKYO 160, JAPAN
[2] AJINOMOTO CO INC, CENT RES LABS, LIFE SCI LABS, YOKOHAMA, KANAGAWA 244, JAPAN
关键词
A-4166; receptor; insulin secretion; sulfonylurea; HIT;
D O I
10.1016/0006-2952(96)00242-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 beta cell line (HIT T-15), using [H-3]A-4166 or [H-3]glibenclamide as a ligand. The saturation binding of [H-3]A-4166 to HIT cell membranes was not observed up to 10 mu M. In the displacement study, unlabeled A-4166 inhibited [H-3]A-4166 binding to HIT cell membranes, but glibenclamide did not. On the other hand, A-4166 inhibited [H-3]glibenclamide binding to the sulfonylurea receptor (K-i = 248 nM). A-4166 inhibited Rb-86 efflux from HIT cells (IC50 = 350 nM). The EC(50) for insulin secretion by A-4166 was 20 mu M 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.
引用
收藏
页码:407 / 411
页数:5
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