| Popis: |
The vasopressin (AVP) antagonist, SKF 101926 (beta-mercapto-beta beta-cyclopentamethylene propionic acid1, D-Tyr(Et)2, Phe3, Val4, Asn5, Cys6, Pro7, Arg8-NH2), is an antidiuretic antagonist in rats and squirrel monkeys in vivo. In rat, dog, pig, squirrel monkey and human in vitro studies, SKF 101926 is an AVP antagonist with no discernable agonist activity. Not predicted by these studies was the discovery that SKF 101926 is an antidiuretic agonist in humans. The purpose of these studies was to show that indomethacin, which potentiates the antidiuretic activity of AVP in hydrated dogs, also potentiates the antidiuretic agonist activity of SKF 101926, and to determine what structural modifications of this AVP antagonist would confer diminished agonist activity. Treatment of dogs with i.v. indomethacin (2 mg/kg bolus + 3 mg/kg/hr infusion, a dose which inhibited 80-90% of the urinary prostaglandin E2 excretion) unmasked the full antidiuretic activity of SKF 101926. SKF 104146 (Arg7-D-Arg8-NH2 peptide tail modification of SKF 101926) in the presence of indomethacin caused a partial antidiuretic response. Replacement of the 1 to 6 disulfide bridge of SKF 104146 with methylene groups to form a "dicarba bridge" resulted in SKF 105494, a compound lacking antidiuretic agonist activity. Using the indomethacin-treated dog model, we have unmasked the full antidiuretic agonist activity of SKF 101926 in nonhumans. In addition, both SKF 104146 and 105494 blocked the antidiuretic agonist activity of SKF 101926, suggesting that the agonist effect seen in the presence of indomethacin treatment is receptor mediated. |
