[1-(beta,beta-Pentamethylene-beta-mercaptopropionic acid),2-(O-ethyl)-D- tyrosine,4-valine,9-desglycine]arginine-vasopressin (SK&F 101926, 1), a potent in vivo and in vitro vasopressin V2 receptor antagonist, was recently tested in human volunteers and shown to be a full antidiuretic agonist. A new animal model for vasopressin activity has been developed in dogs that duplicates the clinical agonist findings exhibited with SK&F 101926. In this model we have discovered that substitution of a cis-4'-methyl group on the Pmp moiety at residue 1 of vasopressin antagonists results in substantially reduced agonist activity compared to the unsubstituted molecule (SK&F 101926). The corresponding analogue with a trans-4'-methyl group exhibits more agonist activity than the cis molecule. These findings can be explained by viewing the biological activities of compounds such as 1 as the interaction of the vasopressin receptor with a number of discrete molecular entities, conformers of 1, which present different pharmacophores. Models have been developed to assist in the understanding of these results.

Vasopressin V2 receptor antagonists of the type first described by Manning et al.2 are distinguished from agonists by, among other things, the requirement for a /3,/3-alkylidene-/3-mercaptopropionic acid moiety at position I.3-4 This substitution introduces several features into the molecule, including increased steric bulk, increased lipo-

1 Vasopressin administration to pentobarbitone-anaesthetized, hydrated female rhesus monkeys resulted in dose-dependent increases in urine osmolality and decreases in urine flow. Treatment with indomethacin at a dose (5 mg kg-1, i.v.) that reduced urinary prostaglandin E2 (PGE2) excretion by at least 70% did not alter these responses. 2 The vasopressin antagonist, SK&F 105494 (Pas" 6D-Tyr(Et)2Val4Arg7D-Arg8desGly9 arginine vasopressin; l0pgkg-1), caused significant rightward shifts (P < 0.05) of both the vasopressin-urine osmolality and the vasopressin-urine flow dose-response curves. Treatment with indomethacin did not alter these responses.3 SK&F 105494 alone or after indomethacin treatment had minimal effects on urine osmolality and urine flow. 4 The data indicate that indomethacin does not alter the antidiuretic activity of vasopressin in the rhesus monkey and that SK&F 105494 is a potent antagonist of exogenous vasopressin with minimal agonist activity.

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Physiological regulation of receptor-effector pathways is recognized as a significant factor determining target organ selectivity and sensitivity in several hormonal systems. Whether or not physiological regulation of the renal vasopressin (V2) receptor-effector pathway participates in the control of body fluid homeostasis is unknown. We evaluated four states likely to be associated with altered sensitivities of the renal V2 receptor-effector pathway as follows: dehydration (18-h hydropenia), volume expansion, exogenous arginine vasopressin (AVP) infusion (10 ng/kg + 0.25 ng.kg-1.h-1), and cyclooxygenase blockade (indomethacin, 2 mg/kg + 2 mg.kg-1.h-1) for effects on the antidiuretic efficacies and potencies of putative V2-receptor antagonists in conscious dogs. The antidiuretic efficacies of desGly9[Pmp1-D-Tyr(Et)2Val4]AVP [Smith Kline & French (SK&F) 101926; 0.01-1,000 micrograms/kg] ranged from that of a full agonist to that of an antagonist, depending on the physiological state studied. The vasopressin antagonist potency of SK&F 101926 was increased 150-fold in association with extracellular volume expansion and decreased by blockade of renal cyclooxygenase activity. This spectrum of activities is that anticipated for a partial agonist under conditions where receptor number and/or sensitivity of receptor-effector coupling is increased or decreased, respectively. Thus volume expansion and increased circulating vasopressin concentration are associated with effective decreases, whereas hydropenia and cyclooxygenase blockade are associated with effective increases in sensitivity of the renal V2 receptor-effector pathway in the dog kidney. We conclude that the V2 receptor-effector pathway is a site of integration of physiological mechanisms participating in the control of body fluid homeostasis in conscious dogs.