title: SK&F 105494: a potent antidiuretic hormone antagonist devoid of partial agonist activity in dogs.
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)
authors.affiliation: Department of Pharmacology, Smith Kline & French Laboratories, Swedeland, Pennsylvania.
authors.forename: N
authors.initials: N
authors.lastname: Caldwell
authors.forename: B
authors.initials: B
authors.lastname: Brickson
authors.forename: L B
authors.initials: LB
authors.lastname: Kinter
authors.forename: D P
authors.initials: DP
authors.lastname: Brooks
authors.forename: W F
authors.initials: WF
authors.lastname: Huffman
authors.forename: F L
authors.initials: FL
authors.lastname: Stassen
authors.forename: C
authors.initials: C
authors.lastname: Albrightson-Winslow
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: C055736:SK&F 105494; D001127:Arginine Vasopressin