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Titolo:
Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4
Autore:
Ahn, JM; Medeiros, M; Trivedi, D; Hruby, VJ;
Indirizzi:
Univ Arizona, Dept Chem, Tucson, AZ 85721 USA Univ Arizona Tucson AZ USA 85721 Arizona, Dept Chem, Tucson, AZ 85721 USA
Titolo Testata:
JOURNAL OF PEPTIDE RESEARCH
fascicolo: 2, volume: 58, anno: 2001,
pagine: 151 - 158
SICI:
1397-002X(200108)58:2<151:DOPGAS>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
HEPATIC ADENYLATE-CYCLASE; SYNTHETIC ANALOGS; RECEPTOR-BINDING; CONFORMATION; PROTEINS; HORMONE; PATHOGENESIS; MEMBRANE; SYSTEM; AMIDE;
Keywords:
alanine; glucagon antagonists; glycine; leucine; structure-activity relationships;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Hruby, VJ Univ Arizona, Dept Chem, Tucson, AZ 85721 USA Univ Arizona Tucson AZ USA 85721 ept Chem, Tucson, AZ 85721 USA
Citazione:
J.M. Ahn et al., "Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4", J PEPT RES, 58(2), 2001, pp. 151-158

Abstract

We examined the functional role of glycine at position 4 in the potent glucagon antagonist [desHis(1), Glu(9)]glucagon amide, by substituting the L- and D-enantiomers of alanine and leucine for Gly(4) in this antagonist. Themethyl and isobutyl sidechain substituents were introduced to evaluate thepreference shown by the glucagon receptor, if any, for the orientation of the N-terminal residues. The L-amino acids demonstrated only slightly better receptor recognition than the D-enantiomers. These results suggest that the Gly4 residue in glucagon antagonists may be exposed to the outside of the receptor. The enhanced binding affinities of analogs 1 and 3 compared with the parent antagonist, [desHis(1), Glu(9)]glucagon amide, may have resulted from the strengthened hydrophobic patch in the N-terminal region and/or the increased propensity for a helical conformation due to the replacement of alanine and leucine for glycine. Thus, as a result of the increased receptor binding affinities, antagonist activities of analogs 1-4 were increased 10-fold compared with the parent antagonist, [desHis(1), Glu(9)]glucagon amide. These potent glucagon antagonists have among the highest pA(2) values of any glucagon analogs reported to date.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 01:05:40