title: Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4.
abstract: We examined the functional role of glycine at position 4 in the potent glucagon antagonist [desHis(1), Glu(9)]glucagon amide, by substituting the L- and D-enantiomers of alanine and leucine for Gly(4) 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 Gly(4) 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, [desHis(1), Glu(9)]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, [desHis(1), Glu(9)]glucagon amide. These potent glucagon antagonists have among the highest pA(2) values of any glucagon analogs reported to date.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson 85721, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Ahn
authors.forename: M
authors.initials: M
authors.lastname: Medeiros
authors.forename: D
authors.initials: D
authors.lastname: Trivedi
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D005934:Glucagon; D000262:Adenylyl Cyclases; D005998:Glycine