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

Abstract

[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.

Orally Active, Nonpeptide Vasopressin V2 Receptor Antagonists: A Novel Series of 1-[4-(Benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepines and Related Compounds

“…Benzene-fused hetero rings (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) were converted into aniline intermediates 17 by the simple transformations shown in Scheme 2. The starting materials were commercially available or were prepared by published procedures.…”

“…AVP antagonists would be expected to be novel therapeutic agents for the treatment of diseases characterized by the excessive renal reabsorption of free water . Until recently, all potent AVP receptor antagonists reported have been peptide analogues of AVP 1-4 and have had poor oral bioavailability, with some exhibiting partial agonistic activity. , Recently, we 8 and others 9 reported orally effective nonpeptide AVP V 1a antagonists.…”

“…4 Until recently, all potent AVP receptor antagonists reported have been peptide analogues of AVP [1][2][3][4] and have had poor oral bioavailability, with some exhibiting partial agonistic activity. 6,7 Recently, we 8 and others 9 reported orally effective nonpeptide AVP V 1a antagonists.…”

Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.

“…Nonetheless, many investigators have modified the structure (11)(12)(13)(14), but have as yet found no nonpeptide V1 / V2 receptor antagonist. Our previous reports (15,16), however, described a nonpeptide, orally active VI receptor antagonist, OPC-21268, and then OPC-31260, a nonpeptide V2 receptor antagonist, also has been developed.…”

Two highly effective V1/V2 antagonists of vasopressin containing novel thioacids at position 1

“…We report here the synthesis and evaluation in rats of two new AVP analogues with dual VI/V2 antagonistic properties. As already mentioned, position 1 of V, antagonists of AVP appears to be extremely important for the peptide-receptor interaction (Huffman et al 1989;Lammek et al 1989). This finding prompted us to design and synthesize new analogues which have at position 1, a novel thioacid with a heteroatom in the cyclohexane ring (Lammek et a1 1990).…”