ACTH Antagonists

Structural modifications within the active site of the ACTH molecule have produced analogs that inhibit the hormone sensitive adenylate cyclase system of bovine adrenal cortical plasma membranes. It is demonstrated that the tryptophan residue of the ACTH molecule is essential for stimulation of the...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1974-01, Vol.71 (1), p.80-83
Main Authors: Hofmann, Klaus, Montibeller, Judith A., Finn, Frances M.
Format: Article
Language:English
Subjects:
Active sites
Adenylyl Cyclases - metabolism
Adrenal Glands - cytology
Adrenal Glands - metabolism
Adrenocorticotropic Hormone - antagonists & inhibitors
Adrenocorticotropic Hormone - metabolism
Adrenocorticotropic Hormone - pharmacology
Amides
Amino Acid Sequence
Animals
Binding Sites
Biological Sciences: Biochemistry
Cattle
Cell Membrane - enzymology
Cell Membrane - metabolism
Cell membranes
Cyclic AMP - biosynthesis
Enzyme Activation
Fluorides
Fluorides - pharmacology
Hormones
In Vitro Techniques
Molecular structure
Molecules
Peptide hormones
Receptors
Receptors, Cell Surface
Stimulation, Chemical
Structure-Activity Relationship
Ungulates
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Description
Summary:Structural modifications within the active site of the ACTH molecule have produced analogs that inhibit the hormone sensitive adenylate cyclase system of bovine adrenal cortical plasma membranes. It is demonstrated that the tryptophan residue of the ACTH molecule is essential for stimulation of the enzyme. Substitution of tryptophan by phenylalanine or by Nα-methyltryptophan as in [Gln5, Phe9]corticotropin1-20amide or [Nα-Metrp9]corticotropin1-24provides ACTH analogs that exhibit high affinity for the ACTH receptor(s) but fail to activate the adenylate cyclase system. It is concluded that affinity for the receptors alone is not sufficient for expression of hormonal activity. The observation that adrenal cortical adenylate cyclase activated by fluoride ion is not inhibited by the antagonists indicates that hormonal and fluoride activation proceed via different mechanisms.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.71.1.80