Glucagon amino groups. Evaluation of modifications leading to antagonism and agonism

M. D. Bregman, D. Trivedi, Victor J Hruby

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Abstract

Using native glucagon and [12-homoarginine]glucagon (analogue A), prepared in high yield and purity by new procedures, we have synthesized the following glucagon analogues by semisynthetic methods: [1-deshistidine][12-homoarginine]glucagon (analogue B); Nα-carbamoylglucagon (analogue C); Nα,Nε-dicarbamoylglucagon (analogue D); [1-Nα-carbamoylhistidine, 12-Nε-trinitrophenyllysine]glucagon (analogue II); [1-deshistidine] [2-Nα-trinitrophenylserine, 12-homoarginine]glucagon (analogue III); and [1-Nα-trinitrophenylhistidine, 12-homoarginine]glucagon (analogue IV). The introduction of hydrophylic groups at the α- and ε-amino positions of glucagon results in a reduction in potency. The α-position is also involved in biological activity. Carbamylation of the α-position results in a partial agonist (analogues C and D). The introduction of hydrophobic groups and the neutralization of the positive charge at the α- and ε-amino positions result in glucagon antagonists (analogues II, III, and IV). [1-Nα-Trinitrophenylhistidine, 12-homoarginine]glucagon (analogue IV) is the most potent inhibitor tested. Based on its competitive inhibitory action, this analogue appears to have about one-third the affinity of glucagon for the receptor site. These modifications at the ε-amino position cause an increase in the secondary structure of the peptide (as shown by circular dichroism studies) which may be related to their biological activities.

Original languageEnglish (US)
Pages (from-to)11725-11731
Number of pages7
JournalJournal of Biological Chemistry
Volume255
Issue number24
StatePublished - 1980

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Glucagon
Bioactivity
Glucagon Receptors
Circular Dichroism
homo-Arg(12)-glucagon
Peptides

ASJC Scopus subject areas

  • Biochemistry

Cite this

Glucagon amino groups. Evaluation of modifications leading to antagonism and agonism. / Bregman, M. D.; Trivedi, D.; Hruby, Victor J.

In: Journal of Biological Chemistry, Vol. 255, No. 24, 1980, p. 11725-11731.

Research output: Contribution to journalArticle

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N2 - Using native glucagon and [12-homoarginine]glucagon (analogue A), prepared in high yield and purity by new procedures, we have synthesized the following glucagon analogues by semisynthetic methods: [1-deshistidine][12-homoarginine]glucagon (analogue B); Nα-carbamoylglucagon (analogue C); Nα,Nε-dicarbamoylglucagon (analogue D); [1-Nα-carbamoylhistidine, 12-Nε-trinitrophenyllysine]glucagon (analogue II); [1-deshistidine] [2-Nα-trinitrophenylserine, 12-homoarginine]glucagon (analogue III); and [1-Nα-trinitrophenylhistidine, 12-homoarginine]glucagon (analogue IV). The introduction of hydrophylic groups at the α- and ε-amino positions of glucagon results in a reduction in potency. The α-position is also involved in biological activity. Carbamylation of the α-position results in a partial agonist (analogues C and D). The introduction of hydrophobic groups and the neutralization of the positive charge at the α- and ε-amino positions result in glucagon antagonists (analogues II, III, and IV). [1-Nα-Trinitrophenylhistidine, 12-homoarginine]glucagon (analogue IV) is the most potent inhibitor tested. Based on its competitive inhibitory action, this analogue appears to have about one-third the affinity of glucagon for the receptor site. These modifications at the ε-amino position cause an increase in the secondary structure of the peptide (as shown by circular dichroism studies) which may be related to their biological activities.

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