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Related Experiment Videos

Synthetic linear and cyclic glucagon antagonists

R Dharanipragada1, D Trivedi, A Bannister

  • 1Department of Chemistry, College of Pharmacy, University of Arizona, Tucson.

International Journal of Peptide and Protein Research
|July 1, 1993
PubMed
Summary

Seven new glucagon analogues were synthesized and tested. Modifications at histidine-1 yielded potent antagonists and partial agonists, enhancing metabolic stability for potential therapeutic applications.

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Area of Science:

  • Medicinal Chemistry
  • Endocrinology
  • Pharmacology

Background:

  • Glucagon receptor antagonists are crucial for managing conditions like type 2 diabetes.
  • Previous research focused on N-terminal modifications of glucagon analogues.
  • Histidine-1 is a key residue for glucagon receptor interaction.

Purpose of the Study:

  • To synthesize and characterize novel glucagon analogues with modifications at histidine-1.
  • To evaluate the biological activities, including receptor binding and adenylate cyclase (AC) activity, of these new analogues.
  • To explore the potential of these analogues as therapeutic agents by assessing their metabolic stability.

Main Methods:

  • Synthesis of seven new glucagon analogues, including linear and cyclic compounds.

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  • N-terminal modifications using unnatural amino acids like (S)-5,6,7,8-tetrahydro-5-oxoimidazo(1,5-c)pyrimidine-7-carboxylic acid (Toc) and desaminohistidine (dHis).
  • Binding assays to determine receptor potency and IC50 values.
  • Fast atom bombardment mass spectrometry for characterization of cyclic analogues.

    • Main Results:

    • Analogues 2, 3, and 5-8 function as glucagon receptor antagonists.
    • Analogue 4 acts as a partial agonist of the adenylate cyclase (AC) system.
    • Cyclic analogues 7 and 8 exhibit biphasic binding curves with nanomolar IC50 values.
    • N-terminal modifications, particularly with Toc, are expected to increase metabolic stability.

    Conclusions:

    • Novel glucagon analogues with modifications at histidine-1 demonstrate significant antagonist or partial agonist activity.
    • The introduction of unnatural amino acids at the N-terminus can enhance metabolic stability.
    • These findings provide a basis for developing improved glucagon-based therapeutics.