@article {Caldwell897, author = {N Caldwell and B Brickson and L B Kinter and D P Brooks and W F Huffman and F L Stassen and C Albrightson-Winslow}, title = {SK\&F 105494: a potent antidiuretic hormone antagonist devoid of partial agonist activity in dogs.}, volume = {247}, number = {3}, pages = {897--901}, year = {1988}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Previous studies from our laboratory have shown that in vivo cyclooxygenase blockade in dogs unmasks the antidiuretic agonist activity associated with the vasopressin antagonist, SK\&F 101926, and have revealed two new vasopressin analogs, SK\&F 104146 and 105494, with greatly reduced antidiuretic agonist activity. The purpose of the present study was to characterize SK\&F 104146 and SK\&F 105494 for water diuretic activity (aquaretic activity) in hydropenic dogs and for antagonism of vasopressin-stimulated antidiuresis in hydrated dogs. The vasopressin receptor affinity and inhibition of vasopressin-stimulated adenylate cyclase activity in renal membranes were also studied. When administered to hydropenic dogs, SK\&F 101926 (3 or 30 micrograms/kg) did not cause a water diuresis. Substitution of the dipeptide tail of SK\&F 101926 with Arg7D-Arg8NH2 (SK\&F 104146; 30 micrograms/kg) was associated with a reduction of urine osmolality from 1876 +/- 182 to 349 +/- 94 mOsm/kg of H2O, and an increase in free water clearance (from -0.32 +/- 0.09 to 0.06 +/- 0.09 ml/min). Replacement of the 1 to 6 disulfide bridge of SK\&F 104146 with a 1 to 6 dicarba bridge (SK\&F 105494; 3 micrograms/kg) was associated with a further reduction of urine osmolality (1709 +/- 281 to 210 +/- 79 mOsm/kg of H2O) and a net positive free water clearance (from -0.56 +/- 0.02 to 0.6 +/- 0.35 ml/min). In water diuretic dogs, SK\&F 104146 and 105494 shifted the vasopressin dose-response for antidiuresis to the right. SK\&F 105494 appeared to be 3 times more potent than SK\&F 104146.(ABSTRACT TRUNCATED AT 250 WORDS)}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/247/3/897}, eprint = {https://jpet.aspetjournals.org/content/247/3/897.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }