Pharmacological Study of IQM-97,423, a Potent and Selective CCK₁ Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis

Abstract

The pharmacological profile of the new CCK₁ receptor antagonist IQM-97,423, (4aS,5R)-2-benzyl-5-(tert-butylaminocarbonyl-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine, was examined in in vitro and in vivo studies and compared with typical CCK₁ antagonists such as devazepide and lorglumide. IQM-97,423 showed a high affinity at [³H]-pCCK₈-labeled rat pancreatic CCK₁ receptors, and was virtually devoid of affinity at brain CCK₂ receptors. IQM-97,423 antagonized CCK_8S-stimulated α-amylase release from rat pancreatic acini with a potency similar to devazepide and much higher than lorglumide. In the guinea pig isolated longitudinal muscle-myenteric plexus preparation, IQM-97,423 produced a full antagonism of the contractile response elicited by CCK_8S and a weaker effect on the contraction elicited by CCK₄, suggesting a selective antagonism at CCK₁ receptors. The protective effect of IQM-97,423 and devazepide was tested in two models of acute pancreatitis in rats, induced by injection of cerulein or by combined bile and pancreatic duct obstruction. The new compound fully prevented the cerulein-induced increase in plasma pancreatic enzymes and in pancreas weight with a potency similar to devazepide. In common bile-pancreatic duct ligature-induced acute pancreatitis, IQM-97,423 partially prevented, like devazepide, the increase in plasma pancreatic enzyme activity and in pancreas weight. Consequently, the pyridopyrimidine derivative IQM-97,423 is a potent and highly selective CCK₁ receptor antagonist with preventive effects in two experimental models of acute pancreatitis and a potential therapeutic interest.