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SK&F 105494: a potent antidiuretic hormone antagonist devoid of partial agonist activity in dogs

N Caldwell, B Brickson, LB Kinter, DP Brooks, WF Huffman, FL Stassen and C Albrightson-Winslow

Department of Pharmacology, Smith Kline & French Laboratories, Swedeland, Pennsylvania.

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)

Volume 247, Issue 3, pp. 897-901, 12/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


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J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1176 - 1183.
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