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W. H. SAWYER, M. ACOSTA, L. BALASPIRI, J. JUDD, M. MANNING, Structural Changes in the Arginine Vasopressin Molecule that Enhance Antidiuretic Activity and Specificity, Endocrinology, Volume 94, Issue 4, 1 April 1974, Pages 1106–1115, https://doi.org/10.1210/endo-94-4-1106
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Three structural changes in the arginine varopressin (AVP) molecule are known to enhance antidiuretic specificity by increasing the ratio of antidiuretic to vasopressor activities (A⁄V ratio). These are: (a) substitution of an amino acid with a smaller and less hydrophilic amino acid side chain for the 4-glutamine, (b) substitution of H for the N-terminal free amino group (deamination) and (c) substitution of Dfor L-arginine in the 8-position. We have synthesized and studied several analogs of AVP in which these three changes have been made singly and in various combinations. We prepared 4- valine analogs since these had not been studied before. Its highly hydrophobic side chain made valine an obvious choice with which to test further the hypothesis that the lipophilic character of the side chain on the amino acid in the 4-position plays a key role in endowing vasopressin analogs with enhanced antidiuretic specificity. Substitution of valine for glutamine did indeed enhance specificity, most strikingly when valine was substituted in peptides containing an 8-D-arginine. When all three changes, (a), (b) and (c) were combined for the first time in a single molecule, 11-deamino, 4-valine, 8-D-arginine]-vasopressin or dVDAVP their effects were cumulative. dVDAVP has undetectable vasopressor activity, antidiuretic activity about four times that of AVP, and an unprecedented A⁄V ratio of over 123,000, compared to 0.9 for AVP. It also has greatly prolonged antidiuretic action in conscious rats. Studies on dVDAVP and related analogs may provide new insights into the structural specificities of AVP receptors and into the mechanisms that terminate antidiuretic responses. (Endocrinology94: 1106, 1974)
