Document Detail

Synthesis of two glucagon antagonists: receptor binding, adenylate cyclase, and effects on blood plasma glucose levels.
MedLine Citation:
PMID:  3039134     Owner:  NLM     Status:  MEDLINE    
In diabetes mellitus, hyperglycemia is often associated with elevated levels of glucagon in the blood. This suggests that glucagon is a contributing factor in the metabolic abnormalities of diabetes mellitus. A glucagon-receptor antagonist would provide direct evidence for glucagon's role in diabetes mellitus. On the basis of careful consideration of conformational, amphiphilic, and structural factors, we have synthesized two new glucagon analogues with antagonist biological activities by using solid-phase methodology. These two new analogues, [Asp3,D-Phe4,Ser5,Lys17,18,Glu21]glucagon (2) and [D-Phe4,Tyr5,3,5-I2-Tyr10,Arg12,Lys17,18,G lu21]glucagon (3) had IC50 values 5.4% and 50% those of glucagon, respectively, and showed no measurable adenylate cyclase activity. When tested in normal rats, 2 lowered plasma glucose levels and suppressed glucagon-mediated hyperglycemia 105 +/- 8%, back to basal levels. Analogue 3, which lowered the basal adenylate cyclase activity in rat liver plasma membranes, increased plasma glucose levels at very high concentration in vivo and inhibited glucagon-mediated hyperglycemia in normal rats by 50%. However, neither of the new glucagon antagonists lowered the plasma glucose levels of diabetic animals. The data would suggest these new glucagon-receptor antagonists may have two actions: (a) in normal rats they can act as standard glucagon-receptor inhibitors of glucagon-mediated glycogenolysis; (b) in diabetic rats, however, because of the low levels of glycogen in the liver, the antagonists apparently have little or no antagonist effect or enhancement on glucagon-mediated glucose production.
B Gysin; D G Johnson; D Trivedi; V J Hruby
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  30     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1987 Aug 
Date Detail:
Created Date:  1987-09-21     Completed Date:  1987-09-21     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1409-15     Citation Subset:  IM    
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MeSH Terms
Adenylate Cyclase / antagonists & inhibitors*
Binding, Competitive
Blood Glucose / metabolism*
Cell Membrane / enzymology
Chemical Phenomena
Diabetes Mellitus, Experimental / blood
Glucagon / analogs & derivatives*,  antagonists & inhibitors,  pharmacology
Liver / enzymology
Rats, Inbred Strains
Receptors, Gastrointestinal Hormone / metabolism*
Receptors, Glucagon
Grant Support
Reg. No./Substance:
0/Blood Glucose; 0/Receptors, Gastrointestinal Hormone; 0/Receptors, Glucagon; 9007-92-5/Glucagon; EC Cyclase

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