Pharmacologic Profile of TS-941, a New Benzodiazepine Derivative Cholecystokinin-Receptor Antagonist, in In Vitro Isolated Rat Pancreatic Acini

Abstract

We investigated the pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-(-)-N-[2,3-dihydro-2-oxo-5-phenyl-1 -[( 1 H-tetrazol-5-yl)methyl]-1 H-1,4-benzodiazepine-3-yl]-2-indolecarboxamide (TS-941), a cholecystokinin type A (CCK-A)-receptor antagonist, in the isolated rat pancreatic acini and compared with those of wellknown CCK-A-receptor antagonists, devazepide and loxiglumide. TS-94 1 inhibited CCK-8-stimulated amylase release concentration dependently, as did devazepide and loxiglumide, with a half-maximal inhibition (IC50) at 78.6 * 10.3 nM. TS-941 was -23 times less potent than devazepide (IC50, 3.4 f 0.3 nM), but was 50 times more potent than loxiglumide (IC50, 3,966 ? 544 nM) in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. TS-941 had a fivefold lower selectivity than devazepide for pancreatic CCK (CCK-A) over brain CCK (CCK-B) receptors but fourfold greater than loxiglumide when IC,, values for inhibition of ['251]CCK-8 binding in isolated acini and cerebral cortex were compared. The antagonism produced by TS-941 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. TS-941 caused a parallel rightward shift of the entire dose-response curve for CCK-8-stimulated amylase release without altering the maximal increase, as did devazepide and loxiglumide. TS-941, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. TS-941 caused a concentrationdependent residual inhibition of the action of CCK-8. The acini, once incubated with a high concentration of TS-941 (10 F M ; 127 times IC50) for 30 min, was 10-fold less sensitive to CCK-8 than the acini preincubated without TS-941, whereas the sensitivity and the responsiveness to CCK-8 stimulation of those incubated with a low concentration of TS-941 (1 .O pA4) were similar to the control acini. These results indicate that TS-941 is a potent, competitive, and selective CCK-A receptor antagonist for the pancreas. Key Words: CCK-A-receptor antagonist-Isolated pancreatic acini-TS-94 1.Recently we demonstrated that the biochemical and histologic alterations in acute pancreatitis are significantly less severe in peripheral cholecystokinin (CCK)-A receptor-deficient rats compared with those in the control rats (1). Until now beneficial effects of the CCK-Areceptor antagonists were demonstrated in seven different models of acute pancreatitis; cerulein-induced ( 2 4 ) , carbamylcholine-induced (9, the CDE diet-induced (6), intraductal infusion of sodium taurocholate (NaTc)-induced (7,8), trauma-induced (9), closed duodenal loop-induced (lo), and pancreatic duct obstructioninduced acute pancreatitis (1 1). In addition, we found a significant increase in plasma CCK levels after acute pancreatitis in both humans and experimental animals (1,12). These results strongly suggest that endogenous CCK and CCK-A receptors play a role in the development of acute pancreatitis. However, the results obtained with specific CC...