SK&F 105494 is a potent antidiuretic hormone antagonist in the rhesus monkey (Macaca mulatta).
The vasopressin analog desGly(CH2)5D-Tyr(Et)VAVP (SK&F 101926) is a potent antagonist of the antidiuretic action of vasopressin in rats, dogs, and squirrel monkeys, demonstrating minimal agonist activity in these species. In humans, however, SK&F 101926 was a potent full antidiuretic agonist. This agonist response was not predicted by in vitro studies with human tissue. The purpose of the present study was to determine if the agonist activity of SK&F 101926 could be modeled in an old-world primate, the rhesus monkey, and, if agonist activity was demonstrated, to determine how SK&F 101926 could be modified to reduce agonist activity and permit the elaboration of antagonist activity in that species. We observed that i.v. administration of SK&F 101926 to the hydrated rhesus monkey resulted in a full antidiuretic agonist response, as observed in humans, and did not reduce urine osmolality or increase urine flow when administered to hydropenic rhesus monkeys. Changing the terminal amino acids from Pro7, Arg8 to Arg7, D-Arg8 produced a compound (SK&F 104146) that was also an agonist, although less potent than SK&F 101926. Further substitution in SK&F 104146 of the sulfide groups of cysteine residues with methyl groups in the peptide ring to produce a "dicarba bridge" resulted in a compound (SK&F 105494) that was associated with minimal agonist activity in hydrated monkeys. Administration of SK&F 105494 (30 micrograms/kg i.v.) reduced urine osmolality from 629 +/- 20 to 91 +/- 7 mosmol/kg H2O (P less than .01) and increased free water clearance to positive levels (from -0.16 +/- 0.03 to 0.73 +/- 0.18 ml/min; P less than .05) in anesthetized hydropenic monkeys.
Brooks
D P
DP
Department of Pharmacology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
Koster
P F
PF
Albrightson-Winslow
C R
CR
Stassen
F L
FL
Huffman
W F
WF
Kinter
L B
LB
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008253:Macaca mulatta; D009318:Natriuresis / Q000187:drug effects; D051381:Rats; D012453:Saimiri; D014667:Vasopressins / Q000037:antagonists & inhibitors* / Q000097:blood
C055736:SK&F 105494; D014667:Vasopressins; D001127:Arginine Vasopressin; C050890:1-((beta-mercapto-beta)beta cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-9-des-Gly-arginine vasopressin; D000262:Adenylyl Cyclases