The role of phenylalanine at position 6 in glucagon's mechanism of biological action: Multiple replacement analogues of glucagon

Bassem Y. Azizeh, Jung Mo Ahn, Rael Caspari, Mark D. Shenderovich, Dev Trivedi, Victor J. Hruby

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Abstract

Extensive evidence gathered from structure-activity relationship analysis has identified and confirmed specific positions in the glucagon sequence that are important either for binding to its receptor or for signal transduction. Fifteen glucagon analogues have been designed and synthesized by incorporating structural changes in the N-terminal region of glucagon, in particular histidine-1, phenylalanine-6, and aspartic acid-9. This investigation was conducted to study the role of phenylalanine at position 6 on the glucagon mechanism of action. These glucagon analogues have been made by either deleting or substituting hydrophobic groups, hydrophilic groups, aromatic amino acids, or a D-phenylalanine residue at this position. The structures of the new analogues are as follows: [des-His1,des- Phe6,Glu9]glucagon-NH2 (1); [des-His1,Ala6Glu9]glucagon-NH2 (2); [des- His1,Tyr6,Glu9]glucagon-NH2 (3); [des-His1,Trp6,Glu9]-glucagon-NH2 (4); [des-His1,D-Phe6,Glu9]glucagon-NH2 (5); [des- His1,Nl36,Glu9]glucagon-NH2 (6); [des-His1,Asp6,Glu9]glucagon-NH2 (7); [des-His1,des-Gly4,Glu9]glucagon-NH2 (8); [des-Phe6,- Glu9]glucagon-NH2 (9); [des-Phe6]glucagon-NH3 (10); [des-His1-,des- Phe6]glucagon-NH2 (11); [des-His1,des-Phe6,Glu9]glucagon (12); [des- Phe6,Glu9]glucagon (13); des-Phe6]glucagon (14); and [des-His1,des- Phe6]glucagon (15). The receptor binding potencies IC50 values are 48 (1), 126 (2), 40 (3), 19 (4), 100 (5), 48 (6), 2000 (7), 52 (8), 113 (9), 512 (10, 128 (11) 1000 (12), 2000 (13), 500 (14), and 200 nM (15). All analogues were found to be antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10-4 M except for analogues 6 and 8, which were found to be weak partial agonists/partial antagonists with maximum stimulation between 6-12%. In competitive inhibition experiments, all the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 8.20 (1), 6.40 (2), 6.20 (3), 6.25 (4), 6.30 (5), 6.30 (7), 6.05 (8), 6.20 (9), 6.30 (10), 6.25 (11), 6.10 (12), 6.20 (13), 6.20 (14), and 6.35 (15).

Original languageEnglish (US)
Pages (from-to)2555-2562
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number16
DOIs
StatePublished - Aug 1 1997

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Glucagon
Phenylalanine
Adenylyl Cyclases
Aromatic Amino Acids
Signal transduction

ASJC Scopus subject areas

  • Organic Chemistry

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The role of phenylalanine at position 6 in glucagon's mechanism of biological action : Multiple replacement analogues of glucagon. / Azizeh, Bassem Y.; Ahn, Jung Mo; Caspari, Rael; Shenderovich, Mark D.; Trivedi, Dev; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 40, No. 16, 01.08.1997, p. 2555-2562.

Research output: Contribution to journalArticle

Azizeh, Bassem Y. ; Ahn, Jung Mo ; Caspari, Rael ; Shenderovich, Mark D. ; Trivedi, Dev ; Hruby, Victor J. / The role of phenylalanine at position 6 in glucagon's mechanism of biological action : Multiple replacement analogues of glucagon. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 16. pp. 2555-2562.
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abstract = "Extensive evidence gathered from structure-activity relationship analysis has identified and confirmed specific positions in the glucagon sequence that are important either for binding to its receptor or for signal transduction. Fifteen glucagon analogues have been designed and synthesized by incorporating structural changes in the N-terminal region of glucagon, in particular histidine-1, phenylalanine-6, and aspartic acid-9. This investigation was conducted to study the role of phenylalanine at position 6 on the glucagon mechanism of action. These glucagon analogues have been made by either deleting or substituting hydrophobic groups, hydrophilic groups, aromatic amino acids, or a D-phenylalanine residue at this position. The structures of the new analogues are as follows: [des-His1,des- Phe6,Glu9]glucagon-NH2 (1); [des-His1,Ala6Glu9]glucagon-NH2 (2); [des- His1,Tyr6,Glu9]glucagon-NH2 (3); [des-His1,Trp6,Glu9]-glucagon-NH2 (4); [des-His1,D-Phe6,Glu9]glucagon-NH2 (5); [des- His1,Nl36,Glu9]glucagon-NH2 (6); [des-His1,Asp6,Glu9]glucagon-NH2 (7); [des-His1,des-Gly4,Glu9]glucagon-NH2 (8); [des-Phe6,- Glu9]glucagon-NH2 (9); [des-Phe6]glucagon-NH3 (10); [des-His1-,des- Phe6]glucagon-NH2 (11); [des-His1,des-Phe6,Glu9]glucagon (12); [des- Phe6,Glu9]glucagon (13); des-Phe6]glucagon (14); and [des-His1,des- Phe6]glucagon (15). The receptor binding potencies IC50 values are 48 (1), 126 (2), 40 (3), 19 (4), 100 (5), 48 (6), 2000 (7), 52 (8), 113 (9), 512 (10, 128 (11) 1000 (12), 2000 (13), 500 (14), and 200 nM (15). All analogues were found to be antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10-4 M except for analogues 6 and 8, which were found to be weak partial agonists/partial antagonists with maximum stimulation between 6-12{\%}. In competitive inhibition experiments, all the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 8.20 (1), 6.40 (2), 6.20 (3), 6.25 (4), 6.30 (5), 6.30 (7), 6.05 (8), 6.20 (9), 6.30 (10), 6.25 (11), 6.10 (12), 6.20 (13), 6.20 (14), and 6.35 (15).",
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TY - JOUR

T1 - The role of phenylalanine at position 6 in glucagon's mechanism of biological action

T2 - Multiple replacement analogues of glucagon

AU - Azizeh, Bassem Y.

AU - Ahn, Jung Mo

AU - Caspari, Rael

AU - Shenderovich, Mark D.

AU - Trivedi, Dev

AU - Hruby, Victor J.

PY - 1997/8/1

Y1 - 1997/8/1

N2 - Extensive evidence gathered from structure-activity relationship analysis has identified and confirmed specific positions in the glucagon sequence that are important either for binding to its receptor or for signal transduction. Fifteen glucagon analogues have been designed and synthesized by incorporating structural changes in the N-terminal region of glucagon, in particular histidine-1, phenylalanine-6, and aspartic acid-9. This investigation was conducted to study the role of phenylalanine at position 6 on the glucagon mechanism of action. These glucagon analogues have been made by either deleting or substituting hydrophobic groups, hydrophilic groups, aromatic amino acids, or a D-phenylalanine residue at this position. The structures of the new analogues are as follows: [des-His1,des- Phe6,Glu9]glucagon-NH2 (1); [des-His1,Ala6Glu9]glucagon-NH2 (2); [des- His1,Tyr6,Glu9]glucagon-NH2 (3); [des-His1,Trp6,Glu9]-glucagon-NH2 (4); [des-His1,D-Phe6,Glu9]glucagon-NH2 (5); [des- His1,Nl36,Glu9]glucagon-NH2 (6); [des-His1,Asp6,Glu9]glucagon-NH2 (7); [des-His1,des-Gly4,Glu9]glucagon-NH2 (8); [des-Phe6,- Glu9]glucagon-NH2 (9); [des-Phe6]glucagon-NH3 (10); [des-His1-,des- Phe6]glucagon-NH2 (11); [des-His1,des-Phe6,Glu9]glucagon (12); [des- Phe6,Glu9]glucagon (13); des-Phe6]glucagon (14); and [des-His1,des- Phe6]glucagon (15). The receptor binding potencies IC50 values are 48 (1), 126 (2), 40 (3), 19 (4), 100 (5), 48 (6), 2000 (7), 52 (8), 113 (9), 512 (10, 128 (11) 1000 (12), 2000 (13), 500 (14), and 200 nM (15). All analogues were found to be antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10-4 M except for analogues 6 and 8, which were found to be weak partial agonists/partial antagonists with maximum stimulation between 6-12%. In competitive inhibition experiments, all the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 8.20 (1), 6.40 (2), 6.20 (3), 6.25 (4), 6.30 (5), 6.30 (7), 6.05 (8), 6.20 (9), 6.30 (10), 6.25 (11), 6.10 (12), 6.20 (13), 6.20 (14), and 6.35 (15).

AB - Extensive evidence gathered from structure-activity relationship analysis has identified and confirmed specific positions in the glucagon sequence that are important either for binding to its receptor or for signal transduction. Fifteen glucagon analogues have been designed and synthesized by incorporating structural changes in the N-terminal region of glucagon, in particular histidine-1, phenylalanine-6, and aspartic acid-9. This investigation was conducted to study the role of phenylalanine at position 6 on the glucagon mechanism of action. These glucagon analogues have been made by either deleting or substituting hydrophobic groups, hydrophilic groups, aromatic amino acids, or a D-phenylalanine residue at this position. The structures of the new analogues are as follows: [des-His1,des- Phe6,Glu9]glucagon-NH2 (1); [des-His1,Ala6Glu9]glucagon-NH2 (2); [des- His1,Tyr6,Glu9]glucagon-NH2 (3); [des-His1,Trp6,Glu9]-glucagon-NH2 (4); [des-His1,D-Phe6,Glu9]glucagon-NH2 (5); [des- His1,Nl36,Glu9]glucagon-NH2 (6); [des-His1,Asp6,Glu9]glucagon-NH2 (7); [des-His1,des-Gly4,Glu9]glucagon-NH2 (8); [des-Phe6,- Glu9]glucagon-NH2 (9); [des-Phe6]glucagon-NH3 (10); [des-His1-,des- Phe6]glucagon-NH2 (11); [des-His1,des-Phe6,Glu9]glucagon (12); [des- Phe6,Glu9]glucagon (13); des-Phe6]glucagon (14); and [des-His1,des- Phe6]glucagon (15). The receptor binding potencies IC50 values are 48 (1), 126 (2), 40 (3), 19 (4), 100 (5), 48 (6), 2000 (7), 52 (8), 113 (9), 512 (10, 128 (11) 1000 (12), 2000 (13), 500 (14), and 200 nM (15). All analogues were found to be antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10-4 M except for analogues 6 and 8, which were found to be weak partial agonists/partial antagonists with maximum stimulation between 6-12%. In competitive inhibition experiments, all the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 8.20 (1), 6.40 (2), 6.20 (3), 6.25 (4), 6.30 (5), 6.30 (7), 6.05 (8), 6.20 (9), 6.30 (10), 6.25 (11), 6.10 (12), 6.20 (13), 6.20 (14), and 6.35 (15).

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