Structure-activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon

Noel S. Sturm, Ann Marie Hutzler, Clinton S. David, Bassem Y. Azizeh, Dev Trivedi, Victor J Hruby

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)293-299
Number of pages7
JournalJournal of Peptide Research
Volume49
Issue number4
StatePublished - 1997

Fingerprint

Glucagon
Amides
Amino Acids
Adenylyl Cyclases
Inhibitory Concentration 50
Glucagon Receptors
Neutral Amino Acids
Molecules

Keywords

  • Glucagon
  • Hinge region
  • Hydrophobic residues
  • Synthetic peptide antagonists

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Sturm, N. S., Hutzler, A. M., David, C. S., Azizeh, B. Y., Trivedi, D., & Hruby, V. J. (1997). Structure-activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon. Journal of Peptide Research, 49(4), 293-299.

Structure-activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon. / Sturm, Noel S.; Hutzler, Ann Marie; David, Clinton S.; Azizeh, Bassem Y.; Trivedi, Dev; Hruby, Victor J.

In: Journal of Peptide Research, Vol. 49, No. 4, 1997, p. 293-299.

Research output: Contribution to journalArticle

Sturm, NS, Hutzler, AM, David, CS, Azizeh, BY, Trivedi, D & Hruby, VJ 1997, 'Structure-activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon', Journal of Peptide Research, vol. 49, no. 4, pp. 293-299.
Sturm, Noel S. ; Hutzler, Ann Marie ; David, Clinton S. ; Azizeh, Bassem Y. ; Trivedi, Dev ; Hruby, Victor J. / Structure-activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon. In: Journal of Peptide Research. 1997 ; Vol. 49, No. 4. pp. 293-299.
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abstract = "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.",
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AU - Hruby, Victor J

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N2 - 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.

AB - 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.

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