title: Potent vasopressin antagonists modified at the carboxy-terminal tripeptide tail.
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.
mesh_terms: D000818:Animals; D008297:Male; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects*; D017483:Receptors, Vasopressin; D013329:Structure-Activity Relationship; D013552:Swine; D014667:Vasopressins / Q000037:antagonists & inhibitors*
chemical_list: D011945:Receptors, Angiotensin; D017483:Receptors, Vasopressin; D014667:Vasopressins