title: Synthetic peptide antagonists of glucagon.
abstract: Several glucagon analogs were synthesized in an effort to find derivatives that would bind with high affinity to the glucagon receptor of rat liver membranes but would not activate membrane-bound adenylate cyclase and, therefore, would serve as antagonists of the hormone. Measurements on a series of glucagon/secretin hybrids indicated that replacement of Asp9 in glucagon by Glu9, found in secretin, was the important sequence difference in the N terminus of the two hormones. Further deletion of His1 and introduction of a C-terminal amide resulted in des-His1-[Glu9]glucagon amide, which had a 40% binding affinity relative to that of native glucagon but caused no detectable adenylate cyclase activation in the rat liver membrane. This antagonist completely inhibited the effect of a concentration of glucagon that alone gave a full agonist response. It had an inhibition index of 12. The pA2 was 7.2. An attempt was made to relate conformation with receptor binding. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C18-silica columns.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D005934:Glucagon / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D018027:Receptors, Glucagon; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005934:Glucagon; D000262:Adenylyl Cyclases