The abilities of the pancreatic cholecystokinin (CCK) receptor antagonists dibutyryl cyclic GMP, proglumide, benzotript, CBZ-tryptophan, CBZ-cysteine and CCK-27-32-amide to inhibit CCK binding to its receptor in the pancreas and brain of mice and guinea pigs was examined. In both species, the same relative potencies of the antagonists in brain and pancreas was seen except that dibutyryl cyclic GMP was considerably more potent on pancreas than on cerebral cortex CCK receptors. CCK-27-32-amide was the most potent inhibitor for both brain and pancreas but was more potent in the guinea pig than in the mouse. Proglumide, a relatively weak antagonist, was a more potent inhibitor of the guinea pig than of the mouse pancreas receptor. Thus, these data suggest that there are both tissue-specific and species-specific differences in CCK antagonist interactions with the CCK receptor.