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 CCK8S-stimulated
alpha-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 CCK8S 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.