Structure-activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon.
We have designed and synthesized eight compounds 2-9 which incorporate neutral, hydrophobic amino acid residues in positions 9, 11 and 16 of the glucagon molecule: (2) [desHis1, Val9. Ile11,16] glucagon amide, (3) [desHis1, Val9,11,16] glucagon amide, (4) [desHis1, Val9, Leu11,16]glucagon amide, (5) [desHis1, Nle9, Ile11,16]glucagon amide, (6) [desHis1, Nle9, Val11,16] glucagon amide, (7) [desHis1,-Nle9, Leu11,16] glucagon amide, (8) [desHis1, Val9, Leu11,16, Lys17,18, Glu21] glucagon amide and (9) [desHis1, Nle9, Leu11,16, Lys17,18, Glu21] glucagon amide. The effect of neutral, hydrophobic residues at positions 9, 11 and 16 led to good binding to the glucagon receptor. Compared to glucagon (IC50 = 1.5 nM), analogues 2-9 were found to have IC50 values of 6.0, 6.0, 11.0, 9.0, 2.5, 2.8, 6.5 and 7.0 nM, respectively. When these compounds were tested for their ability to block adenylate cyclase (AC) activity, they were found to be antagonists having no stimulation of adenyl cyclase, with pA2 values of 6.15, 6.20, 6.30, 7.25, 6.10, 7.30, 6.25 and 7.25, respectively.
Sturm
N S
NS
Department of Chemistry, University of Arizona, Tucson, USA.
Hutzler
A M
AM
David
C S
CS
Azizeh
B Y
BY
Trivedi
D
D
Hruby
V J
VJ
D000067956:Adenylyl Cyclase Inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005934:Glucagon / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D005934:Glucagon