A soluble interaction between dibutyryl cyclic guanosine 3′:5′-monophosphate and cholecystokinin: A possible mechanism for the inhibition of cholecystokinin activity

N²,O^2′-dibutyryl cyclic guanosine 3′:5′-monophosphate has been reported to inhibit the activity of cholecystokinin on several different end organ responses and in several species. Although the mechanism of this inhibition is unclear, competitive antagonism at the level of the receptor has been suggested. We have investigated an alternate possibility, that N²,O^2′-dibutyryl cyclic guanosine 3′:5′-monophosphate inhibits cholecystokinin action by interacting directly with the peptide while both are in solution. We used antisera with specificities for different regions of cholecystokinin-gastrin peptides and radioiodinated cholecystokinin-33, cholecystokinin-8, and gastrin-17. Our results support the possibility of a soluble interaction between N²,O^2′-dibutyryl cyclic guanosine 3′:5′-monophosphate and the peptides of cholecystokinin-gastrin family that is specific for the COOH-terminal (receptor binding) region of these peptides, that is dependent on the concentration of N²,O^2′-dibutyryl cyclic guanosine 3′:5′-monophosphate, and that correlates with concentrations that inhibit biologic activity. The proposed N²,O^2′-dibutyryl cyclic guanosine 3′:5′-monophosphate-cholecystokinin complex is dispersed by gel filtration chromatography, and is prevented from being formed by certain detergents. This soluble interaction may contribute to or explain the inhibition of cholecystokinin activity by N²,O^2′-dibutyryl cyclic guanosine 3′:5′-monophosphate.