Document Report Card

ID: ALA1123570

Journal: J Med Chem

Title: Potent vasopressin antagonists modified at the carboxy-terminal tripeptide tail.

Authors: Ali FE, Chang HL, Huffman WF, Heckman G, Kinter LB, Weidley EF, Edwards R, Schmidt D, Ashton-Shue D, Stassen FL.

Abstract: In a continuing effort to design more potent renal vasopressin (V2 receptor) antagonists, we have focused our attention on the carboxy-terminal tripeptide tail (Pro-Arg-Gly-NH2), a fragment common to both agonists and antagonists. Vasopressin antagonist analogues having a dibasic dipeptide tail, e.g., Arg-Arg-NH2 or Arg-Lys-NH2, attached directly to the cyclic hexapeptide ring are potent V2-receptor antagonists. Similar modification of a representative agonist drastically reduces its potency. We report the synthesis and pharmacological properties of a series of potent V2-receptor antagonists 3-9 where a combination of D or L dibasic dipeptide has been utilized to replace the common tripeptide fragment. Our results suggest a difference in the way agonists and antagonists bind to vasopressin receptor and further support the difference in the structure-activity relationships of agonists and antagonists. These results provide potentially useful insights for the design of novel V2-receptor antagonists.

CiteXplore: 2960813

DOI: 10.1021/jm00395a019