A minor modification of residue 1 in potent vasopressin antagonists dramatically reduces agonist activity

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Abstract
[1-(.beta.,.beta.-Pentamethylene-.beta.-mercaptopropionic acid),2-(O-ethyl)-D-tyrosine,4-valine,9-desglycine]arginine-vasopressing (SK and F 101926, 1) a potent in vivo and in vitro vasopressin V2 receptor antagonist, was recently tested in human volunteers and show to be a full antidiuretic agonist. A new animal model for vasopressing activity has been developed in dogs that duplicates the clinical agonist findings exhibited with SK and 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 and 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.