Design and synthesis of conformationally constrained glucagon analogues

Dev Trivedi, Ying Lin, Jung Mo Ahn, Mara Siegel, Nevena N. Mollova, Karl H. Schram, Victor J. Hruby

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Glucagon was systematically modified by forming lactam bridges within the central region of the molecule to give conformationally constrained cyclic analogues. Six cyclic glucagon analogues have been designed and synthesized. They are c[Asp9,Lys12][Lys17,18,Glu21]glucagon-NH2 (1), c[Asp9,Lys12]glucagon-NH2 (2), c[Lys12,Asp15]glucagon-NH2 (3), c[Asp15,Lys18]glucagon-NH2 (4), [Lys17-c[Lys18,Glu21]glucagon-NH2 (5), and c[Lys12,Asp21]glucagon-NH2 (6). The receptor binding potencies and receptor second messenger activities were determined by radio-receptor binding assays and adenylate cyclase assays, respectively, using rat liver plasma membranes. Most interestingly, analogues 1, 2, 3, and 4 were antagonists of glucagon stimulated adenylate cyclase activity, whereas analogues 5 and 6 were partial agonists in the functional assay. All of the cyclic analogues were found to have reduced binding potencies relative to glucagon. The structural features that might be responsible for these effects were studied using circular dichroism spectroscopy and molecular modeling. These results demonstrated the significant modulations of both receptor binding affinity and transduction (adenylate cyclase activity) that can accompany regional conformational constraints even in larger polypeptide ligands. These studies suggest that the entire molecular conformation, including the flexible middle portion, is important for molecular recognition and transduction at the hepatic glucagon receptor.

Original languageEnglish (US)
Pages (from-to)1714-1722
Number of pages9
JournalJournal of Medicinal Chemistry
Volume43
Issue number9
DOIs
StatePublished - 2000

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Glucagon
Adenylyl Cyclases
Assays
Glucagon Receptors
Circular dichroism spectroscopy
Molecular Conformation
Lactams
Molecular recognition
Molecular modeling
Liver
Second Messenger Systems
Cell membranes
Circular Dichroism
Radio
Conformations
Rats
Spectrum Analysis
Cell Membrane
Modulation
Ligands

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Trivedi, D., Lin, Y., Ahn, J. M., Siegel, M., Mollova, N. N., Schram, K. H., & Hruby, V. J. (2000). Design and synthesis of conformationally constrained glucagon analogues. Journal of Medicinal Chemistry, 43(9), 1714-1722. https://doi.org/10.1021/jm990559d

Design and synthesis of conformationally constrained glucagon analogues. / Trivedi, Dev; Lin, Ying; Ahn, Jung Mo; Siegel, Mara; Mollova, Nevena N.; Schram, Karl H.; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 43, No. 9, 2000, p. 1714-1722.

Research output: Contribution to journalArticle

Trivedi, D, Lin, Y, Ahn, JM, Siegel, M, Mollova, NN, Schram, KH & Hruby, VJ 2000, 'Design and synthesis of conformationally constrained glucagon analogues', Journal of Medicinal Chemistry, vol. 43, no. 9, pp. 1714-1722. https://doi.org/10.1021/jm990559d
Trivedi, Dev ; Lin, Ying ; Ahn, Jung Mo ; Siegel, Mara ; Mollova, Nevena N. ; Schram, Karl H. ; Hruby, Victor J. / Design and synthesis of conformationally constrained glucagon analogues. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 9. pp. 1714-1722.
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