TY - JOUR
T1 - Development of potent glucagon antagonists
T2 - Structure-activity relationship study of glycine at position 4
AU - Ahn, J. M.
AU - Medeiros, M.
AU - Trivedi, D.
AU - Hruby, Victor J.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Alanine
KW - Glucagon antagonists
KW - Glycine
KW - Leucine
KW - Structure-activity relationships
UR - http://www.scopus.com/inward/record.url?scp=0034909040&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034909040&partnerID=8YFLogxK
U2 - 10.1034/j.1399-3011.2001.00880.x
DO - 10.1034/j.1399-3011.2001.00880.x
M3 - Article
C2 - 11532074
AN - SCOPUS:0034909040
SN - 1397-002X
VL - 58
SP - 151
EP - 158
JO - Journal of Peptide Research
JF - Journal of Peptide Research
IS - 2
ER -