We examined the functional role of glycine at position 4 in the potent glucagon antagonist [desHis1, Glu9]glucagon amide, by substituting the L- and D-enantiomers of alanine and leucine for Gly4 in this antagonist. The methyl and isobutyl side-chain substituents were introduced to evaluate the preference shown by the glucagon receptor, if any, for the orientation of the N-terminal residues. The L-amino acids demonstrated only slightly better receptor recognition than the D-enantiomers. These results suggest that the Gly4 residue in glucagon antagonists may be exposed to the outside of the receptor. The enhanced binding affinities of analogs 1 and 3 compared with the parent antagonist, [desHis1, Glu9]glucagon amide, may have resulted from the strengthened hydrophobic patch in the N-terminal region and/or the increased propensity for a helical conformation due to the replacement of alanine and leucine for glycine. Thus, as a result of the increased receptor binding affinities, antagonist activities of analogs 1-4 were increased 10-fold compared with the parent antagonist, [desHis1, Glu9]glucagon amide. These potent glucagon antagonists have among the highest pA2 values of any glucagon analogs reported to date.
- Glucagon antagonists
- Structure-activity relationships
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